TOPIC 5. ORGANIC REACTIONS: ACIDS AND BASES (Chapter 3)

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1 L TPI 5. RGANI REATINS: AIDS AND BASES (hapter 3) BJETIVES 1. lassify types of reaction: -Addition, Substitution, Elimination, Rearrangement 2. Define the concept of Mechanism 3. Discuss the thermodynamics (equilibrium) and kinetics (rate) of organic reactions 4. Describe acid-base reactions 5. Develop relationships between structure and acidity/basicity 6. Take a first look at acid-promoted reactions D.M. ollard 2007

2 LASSIFYING REATINS S:3.1 Reactions are conveniently classified as substitutions, additions, eliminations and rearrangements. These terms describe the overall process, simply comparing the structure of starting materials and products. They do not indicate anything about the pathway ( mechanism ) by which the reaction proceeds. Substitutions Additions Eliminations Rearrangements (often in combination with another type of reaction) Substitution NaI Br acetone (solvent) l pyridine (solvent) D.M. ollard 2007

3 Addition S S 4 Elimination S 4 D.M. ollard 2007

4 Rearrangement 3 3 P A Preview of Reactivity Subst n Subst n Br substitutions additions Add n Add n Elim n Elim n Subst n Subst n substitutions D.M. ollard 2007

5 Practical Aspects of Running a Reaction BEGINNING Starting material ( substrate ) Reagents atalysis (lowers activation energy) Solvent (allows for mixing) Mode of addition Time Temperature (heating/cooling) Environment (avoid 2, 2?) Stirring END Product Byproducts Unreacted reactants atalyst Solvent SEPARATIN PURIFIATIN IDENTIFIATIN % yield = moles of product moles of limiting reactant x 100 Representations of reactions Reactant(s) Product(s) + 2 Substrate (organic starting material) reagent...more commonly written as. Substrate (organic starting material) reagent(s) catalyst(s) solvent(s) Product ( + byproduct(s)) 2,Pt Et 2 2 S 4 D.M. ollard 2007

6 WAT IS A MEANISM? A mechanism is a proposal for a step-by-step pathway by which a reaction proceeds. Each step involves bond making and/or breaking. The mechanism takes into account all currently available evidence (kinetics, formation of byproducts, effect of structure on reactivity). Any new data collected must be consistent with the proposed mechanism, or the mechanism itself must be modified to account for the new finding. An understanding of common mechanistic steps can be applied to new combinations of reagents to predict the outcome of a new reaction. As such, development of an understanding of mechanisms will save you from memorizing a huge amount of material. While you must develop a familiarity with reactions, do not try to pass this course by just memorizing the outcome of reactions! Electrophiles and Nucleophiles Nucleophile Electron-rich, nucleus-loving species Electrophile Electron-deficient, electron-loving species D.M. ollard 2007

7 URVED ARRWS S:3.4 Prob 3.20,25, 31,36,37,40 examples of 2e - processes A B Nu E + A B + Polarity and eterolytic Bond leavage S:3.3 ( 3 ) 3 Br ( 3 ) 3 Br 3 Li 3 Li D.M. ollard 2007

8 Problem 3.20(c). Provide curved arrows to account for the changes in bonding in the following reaction step. F F Problem 3.31(d). Show the curved arrows to account for the following reaction step. 3 I 3 I Problem: Show the curved arrows to account for the following reaction step N N D.M. ollard 2007

9 Problem: What is wrong with each of the following mechanistic steps, suggested by students in previous classes? [consider what the curved arrow is meant to depict, or draw the products of the suggested flow of electrons and comment on why that product is not stable] Br 3 3 N 3 3 l l Br Br Problem: What is wrong with each of the following mechanistic steps suggested by students in previous classes? l l l l D.M. ollard 2007

10 L Definitions AID-BASE REATINS S:3.2; Prob 3.15,17,19, Brønsted Acidity: ability to donate a proton Brønsted Acid: proton donor Brønsted Base: proton acceptor A + :B Strong acids have weak conjugate bases e.g., Acid strength: Br > 2 onjugate base strength: Br < Lewis Acidity Lewis Acid: electron pair acceptor Lewis Base: electron pair donor Ph 3 P: + BF 3 pk a and Acid Strength K eq A + 2 A + 2 acid base conjugate conjugate base acid K eq - + [A ][3 ] = [A][ ] 2 since 2 is solvent, [ 2 ] = 55 M - + [A ][3 ] Ka = [A] K a, acid strength pk a = logk a Bottom line: pk a, acid strength D.M. ollard 2007

11 TE STRENGT F AIDS AND BASES pk a values I S 4-9 Br -9 l -7 ( 3 ) 2 = N F F N N ( 3 ) N = S:3.5 Prob 3.16,18, Species that can act as either an acid or as a base 3 N N pk a = 38 pk a = 15.7 pk a = 10.6 versus 3 N N pk a = 38 pk a = 15.7 pk a = pk a = 5.5 pk a = 15.7 pk a = versus pk a = 5.5 pk a = 15.7 D.M. ollard 2007

12 Amine + Acid N N + 3 pk a = 5.5 pk a = 38 pk a = 10.6 Amino acids 2 N 3 N Amino acids in aqueous solution 3 N 3 N 2 N Predicting Equilibrium onstants K eq A + B: A: + B acid base conjugate conjugate base acid Equilibrium lies of side of the weaker acid and weaker base (the weaker acid and weaker base will always be on the same side) log K eq = pk a (conjugate acid) pk a (acid) K eq = l + Na Nal + 2 pk a = -7 pk a = 15.7 K eq = S S 4 pk a = -9 pk a = -4 D.M. ollard 2007

13 STRUTURE-AIDITY RELATINSIPS S:3.7; 3.8A;3.12 In order to assess the relative strengths of acids, consider the ability of the acid to donate a proton (ability to break the -A bond) and for the conjugate base to accommodate negative charge. Stronger acids have weaker conjugate bases... A + B: A: + B We have ways to assess the ability of ions (anions and cations) to accommodate negative charge based on: Inductive effects (substituents donate or withdraw electron density via sigma bonds) Resonance effects (electron donation or withdrawal by pibonds) ybridization Acidity: Across a Row of the Periodic Table 3 N 2 F pk a conjugate bases 3 N 2 F Bonds strengths are similar: Acidity primarily depends on electronegativity Acidity: Down a olumn of the Periodic Table pk a conjugate base F 3.2 F l -7 l Br -9 Br I -10 I Bonds strength decreases dramatically from -F to -I: Acidity primarily depends on bond strength. D.M. ollard 2007

14 The Effect of Resonance pk a conjugate base Resonance stabilization of conjugate base and increases acidity pka values - 55 Li Be B acid strength N -N F -F 3.2 e Ne Na K Mg a Al Ga Si Ge P As S -S 7.04 Se -Se 3.9 l -l -7 Br -Br -9 acid strength Ar Kr Te -Te 2.6 I -I -10 D.M. ollard 2007

15 The Effect of ybridization Acidity R > R > R 2 2 pk a =25 pk a =44 pk a =50 onjugate bases R R R 2 2 Lone pair in lower energy hybrid orbital stabilizes conjugate base and increases acidity RGANI BASES rganic bases have either lone pairs of electrons or pi-bonding electrons R N l l Strong bases commonly used in organic chemistry: potassium tert-butoxide: K +- ( 3 ) 3 sodium amide: Na + N - 2 sodium hydride: Na + - D.M. ollard 2007

16 The Effect of Structure on Basicity Effect of charge R > R Effect of electronegativity RN 2 > R RN > R Effect of hybridization R 2 N 2 > R N > R N Effect of resonance 3 2 > N 2 > 3 N 2 Effect of alkyl substituents R 3 N > R 2 N > RN 2 > N 3 (gas phase basicity) D.M. ollard 2007

17 AID-BASE REATINS IN AQUEUS AND NN-AQUEUS MEDIA S:3.11; 3.14 Prob 3.38, is the strongest acid, and is strongest base, that can be present in water. l l pk a = -7 pk a = 15.7 pk a = 1.74 Na pk a = 15.7 pk a = 35 In any solvent, the strongest acid [base] which can be present is the conjugate acid [base] of the solvent. The choice of solvent for acid-base reactions is important conjugate conjugate acid base R pk a =25 NaN 2 hexane pk a =55 N 3 pk a =38 R NaN 2 2 pk a =25 pk a =16 N 3 pk a =38 e.g., 3 2+ is the strongest acid possible in methanol (i.e., 2 S 4, a stronger acid, is completely dissociated in methanol). 3 - is the strongest base present in methanol (i.e., N 2-, a stronger base, is completely protonated by methanol). D.M. ollard 2007

18 L PRATIAL APPLIATINS F AID-BASE EMISTRY Separation of Neutral, Acidic and Basic ompounds hallenge: Separate a mixture of hexanoic acid and nonane. Na, 2 Et 2 Na 1. Separate the layers, distill off the ether to isolate nonane 2. Acidify the separated aqueous solution, extract neutral hexanoic acid into another portion of ether. Separate these two layers, remove ether. Neutral organic component in Et 2 sodium carboxylate in aqueous base Problem: Design a procedure to separate hexylamine ( 6 13 N 2 ) from nonane. Provide Greater Water-solubility to Drugs Naproxen sodium (Aleve) 3 Na 3 Na + 2 Go directly to jail.. 3 N 3 N l 3 l 3 Ph Na 2 3 Ph D.M. ollard 2007

19 atalysis of Reactions Proton transfer is usually fast. Protonation (or deprotonation) of an organic starting material with an acid (or base) often catalyzes reactions which do not take place in the absence of catalyst. Bases deprotonate molecules and make them better (i.e., more reactive) nucleophiles Acids protonate molecules and make them better electrophiles ENERGY ANGES AND EQUILIBRIA: TERMDYNAMIS S: Prob 3.35 Equilibria K eq [products] Reactants (R) Products (P) K eq = [reactants] Enthalpy Δ = products reactants based on changes in bonding D.M. ollard 2007

20 alculating eats of Reaction, Δ kcal mol -1 bonds broken bonds made net change (energy IN) (energy UT) organic stuff,, (+N,S,P,...) 2 == + 2 Representative Bond Lengths and Strengths bond length bond strength Ǻ kcal/mol kj/mol F l Br I = = F l Br I Ǻ = m = 100 pm 1 kcal = 4.18 kj D.M. ollard 2007

21 Problem. alculate the Δ for the following reaction Br 3 Br 3 3 Relationship Between K eq and ΔG Equilibrium constant depends on changes in enthalpy and entropy (change in disorder) hange in Gibbs free energy for a reaction: ΔG = Δ T ΔS P ΔG = G products G reactants ΔG = RT lnk eq = RT logk eq R = J/K.mol = cal/k.mol T = temperature (in K) G R ΔG > 0 (positive) endothermic K eq = [products] / [reactants] When ΔG = 0; K eqm eqm R When ΔG >0; K eqm When ΔG < 0; K eqm If ΔG < -13 kj mol -1, K >100 eqm G ΔG < 0 (negative) exothermic P D.M. ollard 2007

22 For the equilibrium: ΔG o = RT lnk eq = RT logk eq A B ΔG o (kcal/mol) K eq % A at equilibrium % A ΔG (kcal/mol)» A small change in the Δ of a reaction has a large influence on K eq If ΔG < -13 kj mol -1, K >100 Thermodynamics tells us the extent to which a reaction AN occur, but nothing about how FAST it will be KINETIS Transition State Theory: Energy-Reaction oordinate Diagram for a ne-step Reaction Energy R P Energy Energy Reaction oordinate Reaction oordinate Reaction oordinate Rate constant: k = Ae -E a/rt atalysis - D.M. ollard 2007

23 k = Ae -E a /RT Effect of E a on Rate (at 25 ) E a kcal/mol logk (i.e., krel=1) Effect of Temperature on Rate For reaction: A B (for E a = 25 kcal/mol) T/ k rel logk rel k rel E a (kcal/mol) » A small change in the E a of a reaction has a very large influence on k» A small increase in temperature can have a large influence on k T/ Energy-Reaction oordinate Diagram for Two-Step Reaction Reactants Intermediate Product Energy Reaction oordinate D.M. ollard 2007

24 A MULTISTEP MEANISM IN WI TE FIRST STEP IS AN AID-BASE REATIN S:3.13 Substitution of tert-butyl Alcohol verall Reaction Br Br ow do changes in bonding take place? Mechanism Protonation Br eterolytic leavage Nucleophilic Addition Br D.M. ollard 2007

25 TPI 5 FR EXAM 3 Types of Questions - lassify organic reactions - ompare acid (or base) strength - Show movement of electrons The problems in the book are good examples of the types of problems on the exam! Preparing for Exam 3: - Get up to date now! - Work as many problems as possible - Work in groups - Do the Learning Group Problem at the end of the chapter D.M. ollard 2007