Ciências Farmacêuticas Bioquímica Química AFB QO I 2007/08 1

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1 Química Orgânica I Ciências Farmacêuticas Bioquímica Química AFB QO I 2007/08 1 Adaptado de: Organic Chemistry, 6th Edition; L. G. Wade, Jr. Organic Chemistry, 6 th edition; McMurry s AFB QO I 2007/08 2 1

2 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 AFB QO I 2007/08 3 An Addition Reaction AFB QO I 2007/08 4 2

3 An Elimination Reaction AFB QO I 2007/08 5 A Substitution Reaction AFB QO I 2007/08 6 3

4 A Rearrangement Reaction AFB QO I 2007/08 7 How Organic Reactions Occur Mechanisms 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 AFB QO I 2007/08 8 4

5 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 AFB QO I 2007/08 9 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 AFB QO I 2007/

6 Homogenic Formation of a Bond One electron comes from each fragment No electronic charges are involved AFB QO I 2007/08 11 Homogenic Formation of a Bond AFB QO I 2007/

7 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 AFB QO I 2007/08 13 Heterogenic Formation of a Bond AFB QO I 2007/

8 Indicating Steps in Mechanisms Curved arrows indicate breaking and forming of bonds Arrowheads with a half head ( fish-hook ) indicate homolytic and 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 AFB QO I 2007/08 15 Bond Making AFB QO I 2007/

9 Homolytic Breaking of Covalent Bonds Each product gets one electron from the bond AFB QO I 2007/08 17 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 AFB QO I 2007/

10 Bond Breaking AFB QO I 2007/08 19 Radicals A free radical is an R group on its own: CH 3 is a free radical or simply radical Has a single unpaired electron, shown as: CH 3. Its valence shell is one electron short of being complete AFB QO I 2007/

11 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 AFB QO I 2007/08 21 Radical Substitution AFB QO I 2007/

12 Radical Addition AFB QO I 2007/08 23 Chlorination of methane: a radical substitution reaction AFB QO I 2007/

13 Steps in Radical Substitution Intitiation AFB QO I 2007/08 25 Steps in Radical Substitution Propagation AFB QO I 2007/

14 Steps in Radical Substitution Termination AFB QO I 2007/08 27 Polar Reactions Polarity AFB QO I 2007/

15 Polarity is affected by structure changes: AFB QO I 2007/08 29 AFB QO I 2007/

16 AFB QO I 2007/08 31 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 AFB QO I 2007/

17 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 AFB QO I 2007/08 33 Polar Reactions: AFB QO I 2007/

18 Electrophiles & Nuclephiles AFB QO I 2007/08 35 a Polar Reaction: Addition of HBr to Ethylene AFB QO I 2007/

19 Addition of HBr to Ethylene δ+ H Br AFB QO I 2007/08 37 Π-Bonds as Nucleophiles: Π-bonding electron pairs can function as Lewis bases: AFB QO I 2007/

20 Mechanism of Addition of HBr to Ethylene AFB QO I 2007/08 39 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 AFB QO I 2007/

21 electrons move from Nu: to E AFB QO I 2007/08 41 Nu: can be negative or neutral AFB QO I 2007/

22 E can be positive or neutral AFB QO I 2007/08 43 ELECTRONS AND CHARGES AFB QO I 2007/

23 curved arrows? AFB QO I 2007/08 45 Solution: AFB QO I 2007/

24 Describing a Reaction: Equilibria, Rates, and Energy Changes aa + bb cc + dd K eq = [Products]/[Reactants] = [C] c [D] d / [A] a [B] b AFB QO I 2007/08 47 Keq AFB QO I 2007/

25 Numeric Relationship of K eq and Free Energy Change The standard free energy change at 1 atm pressure and 298 K is Gº The relationship between free energy change and an equilibrium constant is: Gº = -RT lnk eq where R = cal/(k x mol) (gas constant) T = temperature in Kelvins ln = natural logarithm AFB QO I 2007/08 49 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 AFB QO I 2007/

26 Ethylene + HBr Gº = Hº - T Sº AFB QO I 2007/08 51 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 AFB QO I 2007/

27 Calculation of an Energy Change from Bond Dissociation Energies AFB QO I 2007/08 53 Describing a Reaction: Energy Diagrams and Transition States AFB QO I 2007/

28 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 ) AFB QO I 2007/08 55 First Step in the Addition of HBr AFB QO I 2007/

29 Formation of a Carbocation Intermediate 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 AFB QO I 2007/08 57 Carbocation Intermediate Reactions with Anion Bromide ion adds an electron pair to the carbocation An alkyl halide produced The carbocation is a reactive intermediate AFB QO I 2007/

30 AFB QO I 2007/08 59 Chlorination of Methane AFB QO I 2007/

31 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). AFB QO I 2007/08 61 Initiation Step A chlorine molecule splits homolytically into chlorine atoms (free radicals). AFB QO I 2007/

32 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). AFB QO I 2007/08 63 Propagation Step (2) The methyl free radical collides with another chlorine molecule, producing the other product (methyl chloride) and regenerating the chlorine radical. AFB QO I 2007/

33 Overall Reaction AFB QO I 2007/08 65 Termination Steps Collision of any two free radicals. Combination of free radical with contaminant or collision with wall. Can you suggest others? AFB QO I 2007/

34 Equilibrium Constant K eq = [products] [reactants] For chlorination K eq = 1.1 x Large value indicates reaction goes to completion. AFB QO I 2007/08 67 Free Energy Change G = free energy of (products - reactants), amount of energy available to do work. Negative values indicate spontaneity. G o = -RT(lnK eq ) where R = J/K-mol and T = temperature in kelvins Since chlorination has a large K eq, the free energy change is large and negative. AFB QO I 2007/

35 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? AFB QO I 2007/08 69 Kinetics Answers question, How fast? Rate is proportional to the concentration of reactants raised to a power. Rate law is experimentally determined. AFB QO I 2007/

36 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 ratedetermining step of the mechanism. The value of k depends on temperature as given by Arrhenius: k E a / RT r = Ae AFB QO I 2007/08 71 Activation Energy Minimum energy required to reach the transition state. At higher temperatures, more molecules have the required energy. H H C H H Cl AFB QO I 2007/

37 Energy Diagram Reactants transition state intermediate Intermediate transition state product AFB QO I 2007/08 73 Rate, E a, and Temperature X + CH 4 HX + CH 3 X E a 300K 500K F 5 kj 140, ,000 Cl 17 kj ,000 Br 75 kj 9 x I 140 kj 2 x x 10-9 AFB QO I 2007/

38 Conclusions With increasing E a, 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). AFB QO I 2007/08 75 Chlorination of Propane 1 C CH 3 CH 2 C 2 CH 3 + Cl hν 2 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. Cl CH 2 Cl CH 2 CH 3 + CH 3 CH CH 3 AFB QO I 2007/

39 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. AFB QO I 2007/08 77 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 AFB QO I 2007/

40 Chlorination Energy Diagram Lower E a, faster rate, so more stable intermediate is formed faster. AFB QO I 2007/08 79 Bromination of Propane 1 C Br CH 3 CH 2 CH 3 + Br 2 heat CH 2 2 C 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 CH 2 CH 3 + CH 3 Bromination is more selective than AFB chlorination. QO I 2007/08 80 Br CH CH 3 40

41 compare hydrogen reactivity 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 H 97% 2 = 48.5% per secondary H Secondary H s are 48.5% 0.5% = 97 times more reactive toward bromination than primary H s. AFB QO I 2007/08 81 Bromination Energy Diagram BDE for HBr is 368 kj, but 431 kj for HCl AFB QO I 2007/

42 Bromination vs. Chlorination AFB QO I 2007/08 83 Endothermic and Exothermic Diagrams AFB QO I 2007/

43 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. AFB QO I 2007/08 85 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. AFB QO I 2007/

44 Reactive Intermediates Carbocations Free radicals Carbanions Carbene AFB QO I 2007/08 87 Carbocation Structure Carbon has 6 electrons, positive charge. Carbon is sp 2 hybridized with vacant p orbital. AFB QO I 2007/

45 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 p orbital. AFB QO I 2007/08 89 Free Radicals Also electron-deficient Stabilized by alkyl substituents Order of stability: 3 > 2 > 1 > methyl AFB QO I 2007/

46 Carbanions Eight electrons on C: 6 bonding + lone pair Carbon has a negative charge Destabilized by alkyl substituents Methyl >1 > 2 > 3 AFB QO I 2007/08 91 Carbenes Carbon is neutral. Vacant p orbital, so can be electrophilic. Lone pair of electrons, so can be nucleophilic. AFB QO I 2007/