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AFB QO I 2007/08 1

Química Orgânica I

Ciências Farmacêuticas

Bioquímica

Química

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Adaptado de:

� Organic Chemistry, 6th Edition; L. G. Wade, Jr.

� Organic Chemistry, 6th edition; McMurry’s

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5.1 Kinds of Organic Reactions

� Addition reactions – two molecules combine

� Elimination reactions – one molecule splits into two

� Substitution – parts from two molecules exchange

� Rearrangement reactions – a molecule undergoes changes in the way its atoms are connected

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An Addition Reaction

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An Elimination Reaction

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A Substitution Reaction

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A Rearrangement Reaction

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How Organic Reactions OccurMechanisms

� In a clock the hands move but the mechanism behind the face is what causes the movement

� In an organic reaction, by isolating and identifying the products, we see the transformation that has occurred.

� The mechanism describes the steps behind the changes that we can observe

� Reactions occur in defined steps that lead from reactant to product

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Steps in Mechanisms

� A step usually involves either the formation or breaking of a covalent bond

� Steps can occur individually or in combination with other steps

� When several steps occur at the same time they are said to be concerted

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Types of Steps in Reaction Mechanisms

� Formation of a covalent bond

� Homogenic or heterogenic

� Breaking of a covalent bond

� Homolytic or heterolytic

� Oxidation of a functional group

� Reduction of a functional group

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Homogenic Formation of a Bond

�One electron comes from each fragment

�No electronic charges are involved

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Homogenic Formation of a Bond

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Heterogenic Formation of a Bond

� One fragment supplies two electrons (Lewis Base)

� One fragment supplies no electrons (Lewis Acid)

� Combination can involve electronic charges

� Common in organic chemistry

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Heterogenic Formation of a Bond

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Indicating Steps in Mechanisms

� Curved arrows indicate breaking and forming of bonds

� Arrowheads with a “half” head (“fish-hook”) indicate homolyticand homogenic steps (called ‘radical processes’)—the motion of one electron

� Arrowheads with a complete head indicate heterolytic and heterogenic steps (called ‘polar processes’)—the motion of an electron pair

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Bond Making

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Homolytic Breaking of Covalent Bonds

�Each product gets one electron from the bond

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Heterolytic Breaking of Covalent Bonds

� Both electrons from the bond that is broken become associated with one resulting fragment

� A common pattern in reaction mechanisms

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Bond Breaking

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Radicals

� A “free radical” is an “R” group on its own:� CH3 is a “free radical” or simply “radical”

� Has a single unpaired electron, shown as: CH3

.

� Its valence shell is one electron short of being complete

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Radical Reactions

�Radicals react to complete electron octet of valence shell� A radical can break a bond in another

molecule and abstract a partner with an electron, giving substitution in the original molecule

� A radical can add to an alkene to give a new

radical, causing an addition reaction

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Radical Substitution

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Radical Addition

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Chlorination of methane: a radical substitution reaction

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Steps in Radical SubstitutionIntitiation

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Steps in Radical SubstitutionPropagation

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Steps in Radical SubstitutionTermination

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Polar ReactionsPolarity

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Polarity is affected by structure changes:

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Polarizability

� Polarization is a change in electron distribution as a response to change in electronic nature of the surroundings

� Polarizability is the tendency to undergo polarization

� Polar reactions occur between regions of high electron density and regions of low electron density

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Generalized Polar Reactions

� An electrophile, an electron-poor species (Lewis acid), combines with a nucleophile, an electron-rich species (Lewis base)

� The combination is indicated with a curved arrow from nucleophile to electrophile

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Polar Reactions:

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Electrophiles & Nuclephiles

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a Polar Reaction: Addition of HBr to Ethylene

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Addition of HBr to Ethylene

HBr

δ+

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Π-Bonds as Nucleophiles:

� Π-bonding electron pairs can function as Lewis bases:

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Mechanism of Addition of HBr to Ethylene

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Rules for Using Curved Arrows

� The arrow goes from the nucleophilic reaction site to the electrophilic reaction site

� The nucleophilic site can be neutral or negatively charged

� The electrophilic site can be neutral or positively charged

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electrons move from Nu: to E

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Nu: can be negative or neutral

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E can be positive or neutral

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ELECTRONS AND CHARGES

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curved arrows?

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Solution:

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Describing a Reaction: Equilibria, Rates, and Energy Changes

aA + bB cC + dD

Keq = [Products]/[Reactants] = [C]c [D]d / [A]a[B]b

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Keq

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Numeric Relationship of Keq and Free Energy Change

� The standard free energy change at 1 atmpressure and 298 K is ∆Gº

� The relationship between free energy change and an equilibrium constant is:

� ∆∆∆∆Gº = - RT lnKeq where

� R = 1.987 cal/(K x mol) (gas constant)

� T = temperature in Kelvins

� ln = natural logarithm

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Changes in Energy at Equilibrium

� Free energy changes (∆Gº) can be divided into� a temperature-independent part called entropy (∆Sº) that measures the change in the amount of disorder in the system

� a temperature-dependent part called enthalpy (∆Hº) that is associated with heat given off (exothermic) or absorbed (endothermic)

� ∆∆∆∆Gº = ∆∆∆∆Hº - T∆∆∆∆Sº

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Ethylene + HBr

∆Gº = ∆Hº - T∆Sº

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Describing a Reaction: Bond Dissociation Energies

� Bond dissociation energy (D): Heat change that occurs when a bond is broken by homolysis

� The energy is mostly determined by the type of bond, independent of the molecule

� The C-H bond in methane requires a net heat input of 105 kcal/mol to be broken at 25 ºC.

� Changes in bonds can be used to calculate net changes in heat

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Calculation of an Energy Change from Bond Dissociation Energies

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Describing a Reaction: Energy Diagrams and Transition States

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Describing a Reaction: Energy Diagrams and Transition States

� The highest energy point in a reaction step is called the transition state

� The energy needed to go from reactant to transition state is the activation energy (∆G‡)

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First Step in the Addition of HBr

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Formation of a CarbocationIntermediate

� HBr, a Lewis acid, adds to the π bond

� This produces an intermediate with a positive charge on carbon - a carbocation

� This is ready to react with bromide

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Carbocation Intermediate Reactions with Anion

� Bromide ion adds an electron pair to the carbocation

� An alkyl halide produced

� The carbocation is a reactive intermediate

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� Chlorination of Methane

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Chlorination of Methane

� Requires heat or light for initiation.

� The most effective wavelength is blue, which is absorbed by chlorine gas.

� Many molecules of product are formed from absorption of only one photon of light (chain reaction).

=>

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Initiation Step

A chlorine molecule splits homolyticallyinto chlorine atoms (free radicals).

=>

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Propagation Step (1)

The chlorine atom collides with a methane molecule and abstracts (removes) a H, forming another free radical and one of the products (HCl).

=>

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Propagation Step (2)

The methyl free radical collides with another chlorine molecule, producing the other product (methyl chloride) and regenerating the chlorine radical.

=>

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Overall Reaction

=>

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Termination Steps� Collision of any two free radicals.

� Combination of free radical with contaminant or collision with wall.

Can you suggest others? =>

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Equilibrium Constant

� Keq = [products][reactants]

� For chlorination Keq = 1.1 x 1019

� Large value indicates reaction “goes to completion.”

=>

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Free Energy Change

� ∆G = free energy of (products -reactants), amount of energy available to do work.

� Negative values indicate spontaneity.

� ∆Go = -RT(lnKeq)where R = 8.314 J/K-moland T = temperature in kelvins

� Since chlorination has a large Keq, the free energy change is large and negative.

=>

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Problem

� Given that -X is -OH, the energy difference for the following reaction is -4.0 kJ/mol.

� What percentage of cyclohexanol molecules will be in the equatorial conformer at equilibrium at 25°C?

=>

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Kinetics

� Answers question, “How fast?”

� Rate is proportional to the concentration of reactants raised to a power.

� Rate law is experimentallydetermined.

=>

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Reaction Order� For A + B → C + D, rate = k[A]a[B]b

� a is the order with respect to A

� b is the order with respect to B

� a + b is the overall order

� Order is the number of molecules of that reactant which is present in the rate-determining step of the mechanism.

� The value of k depends on temperature as given by Arrhenius:

RTEaAek

/

r

−= =>

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Activation Energy

� Minimum energy required to reach the transition state.

� At higher temperatures, more molecules have the required energy.

C

H

H

H

H Cl

=>

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Energy Diagram� Reactants → transition state → intermediate

� Intermediate → transition state → product

=>

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Rate, Ea, and Temperature

X + CH4 HX + CH3

X E a Rate @ 300K Rate @ 500K

F 5 kJ 140,000 300,000

Cl 17 kJ 1300 18,000

Br 75 kJ 9 x 10-8

0.015

I 140 kJ 2 x 10-19

2 x 10-9

=>

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Conclusions

� With increasing Ea, rate decreases.

� With increasing temperature, rate increases.

� Fluorine reacts explosively.

� Chlorine reacts at a moderate rate.

� Bromine must be heated to react.

� Iodine does not react (detectably).

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Chlorination of Propane

� six 1° H’s; two 2° H’s. � We expect 3:1 product mix,

� 75% 1-chloropropane

� 25% 2-chloropropane.

� Typical product mix: � 40% 1-chloropropane

� 60% 2-chloropropane.

� Therefore, not all H’s are equally reactive.

=>

1°°°° C

2°°°° CCH3 CH2 CH3 + Cl2

hννννCH2

Cl

CH2 CH3 + CH3 CH

Cl

CH3

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compare hydrogen reactivity

� find amount of product formed per hydrogen: � 40% 1-chloropropane from 6 hydrogens� 60% 2-chloropropane from 2 hydrogens.

� 40% ÷÷÷÷ 6 = 6.67% per primary H� 60% ÷÷÷÷ 2 = 30% per secondary H

� Secondary H’s are 30% ÷÷÷÷ 6.67% = 4.5 times more reactive toward chlorination than primary H’s. =>

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Free Radical Stabilities� Energy required to break a C-H bond

decreases as substitution on the carbon increases.

� Stability: 3° > 2° > 1° > methyl∆H(kJ) 381, 397, 410, 435

=>

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Chlorination Energy DiagramLower Ea, faster rate, so more stable

intermediate is formed faster.

=>

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� six 1° H’s and two 2° Η’s. � We expect 3:1 product mix, or

� 75% 1-bromopropane

� 25% 2-bromopropane.

� Typical product mix: � 3% 1-bromopropane

� 97% 2-bromopropane

� Bromination is more selective than chlorination. =>

1°°°° C

2°°°° C

CH3 CH2 CH3 + CH2

Br

CH2 CH3 +Br2

heatCH3 CH

Br

CH3

Bromination of Propane

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� find amount of product formed per H:� 3% 1-bromopropane from 6 hydrogens

� 97% 2-bromopropane from 2 hydrogens.

� 3% ÷÷÷÷ 6 = 0.5% per primary H97% ÷÷÷÷ 2 = 48.5% per secondary H

� Secondary H’s are 48.5% ÷÷÷÷ 0.5% = 97 times more reactive toward bromination than primary H’s.

compare hydrogen reactivity

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Bromination Energy Diagram

� BDE for HBr is 368 kJ, but 431 kJ for HCl

=>

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Bromination vs. Chlorination

=>

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Endothermic and Exothermic Diagrams

=>

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Hammond Postulate

� Related species that are similar in energy are also similar in structure. The structure of a transition state resembles the structure of the closest stable species.

� Endothermic reaction: transition state is product-like.

� Exothermic reaction: transition state is reactant-like.

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Radical Inhibitors

� Often added to food to retard spoilage.

� Without an inhibitor, each initiation step will cause a chain reaction so that many molecules will react.

� An inhibitor combines with the free radical to form a stable molecule.

� Vitamin E and vitamin C are thought to protect living cells from free radicals.

=>

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Reactive Intermediates� Carbocations

� Free radicals

� Carbanions

� Carbene

=>

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Carbocation Structure

� Carbon has 6 electrons, positive charge.

� Carbon is sp2 hybridized with vacant porbital.

=>

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Carbocation Stability

� Stabilized by alkyl substituents 2 ways:

� (1) Inductive effect: donation of electron density along the sigma bonds.

� (2) Hyperconjugation: overlap of sigma bonding orbitals with empty porbital.

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Free Radicals

� Also electron-deficient

� Stabilized by alkyl substituents

� Order of stability:3° > 2° > 1° > methyl =>

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Carbanions� Eight electrons on C:

6 bonding + lone pair

� Carbon has a negative charge

� Destabilized by alkyl substituents

� Methyl >1° > 2 ° > 3 °

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Carbenes

� Carbon is neutral.

� Vacant p orbital, so can be electrophilic.

� Lone pair of electrons, so can be nucleophilic. =>