Lecture 18 Organic Chemistry 1

Transcription

1 CEM 232 rganic Chemistry I at Chicago Lecture 18 rganic Chemistry 1 Professor Duncan Wardrop March 9,

2 Nucleophilicity nucleophilicity: measures the strength of the nucleophile ; more nucleophilic = faster SN2 reaction 1. for identical atoms, more basic = more nucleophilic 3 C (conjugate acid) pka = 15.2 is more nucleophilic than (stronger base = stronger nuc) 3 C C 2 (conjugate acid) pka = 4.7 Slide 2 2

3 Nucleophilicity nucleophilicity: measures the strength of the nucleophile ; more nucleophilic = faster SN2 reaction 2. For atoms in the same row and with same charge, nucleophilicity decreases left to right 3 C N 2 is more nucleophilic than (stronger base = stronger nuc) N 3 + (conjugate acid) pka = C 2 + (conjugate acid) pka = -2 Slide 3 3

4 Nucleophilicity nucleophilicity: measures the strength of the nucleophile ; more nucleophilic = faster SN2 reaction 3. Nucleophilicity does not follow basicity down a column; nucleophilicity increase down a column 3 C S is more nucleophilic than 3 C I is more nucleophilic than Br Slide 4 4

5 Explanation for alide Nucleophilicity small anions = high charge to size ratio = ion-dipole forces between halide and solvent strongest for F and weakest for I = F more solvated more difficult for F to shed solvent molecules to react with electrophile = weaker nucleophile Slide 5 5

6 Self-Test Question All of the molecules/anions below are strong bases. owever, each is non-nucleophilic; they do not participate in SN2 reactions. Why? N N A. large van der Waals radius B. unstable; decompose rapidly N N Si N Si C. each atom already satisfies octet rule; can t form more bonds D. nucleophiles must be neutral sterically hindered = non-nucleophilic E. too highly solvated University of Illinois at Chicago CEM 232, Spring 2010 Slide 6 6

7 CEM 232 rganic Chemistry I at Chicago Chapter 8 SN1 Mechanism of Nucleophilic Substitution Sections

8 Self-Test Question Which potential energy diagram best describes the substitution reaction of 1-bromo-1-methylcyclohexane with a cyanide nucleophile. int: 3º alkyl halides do not proceed through an SN2 mechanism. Br NC CN University of A B C D Illinois at Chicago CEM 232, Spring 2010 Slide 8 8

9 Tertiary Alkyl alides Do Not Proceed Through an SN2 Mechanism Slide 9 9

10 SN1 Mechanism Br C N NC δ Br δ + N C δ δ + C-LG bond breaks first; rate determining step (RDS) form carbocation intermediate Br NC nucleophile adds rapidly to carbocation rate = k[alkyl halide] unimolecular Slide 10 10

11 SN1 Mechanism: Solvolysis When the nucleophile undergoing either SN1 or SN2 is a molecule of the solvent, the process is called solvolysis Br solvent + solvent Br + 2 hydrolysis Br 3 C + methanolysis Br 2 N + N 3 ammonolysis Slide 11 11

12 SN1 Mechanism: Solvolysis Br 2 C3 2 carbocation oxonium ion Br Br δ δ + δ + δ + solvent acts as nucleophile (neutral) same mechanism extra deprotonation step at the end (fast) any Bronsted base in solution can perform the deprotonation (here = 2 or Br ) Slide 12 12

13 Rate of SN1 vs. SN2 Slide 13 13

14 SN1 Mechanism Br C N NC Br δ Br δ + N C δ δ + NC ammond Postulate: late transition state (TS) = TS is similar in structure to carbocation intermedate = what stabilizes carbocation will also stabilize the TS lower energy TS = faster reaction What lowers the energy of carbocations and thus the TS? Slide 14 14

15 Review: Carbocation Stability 1. Inductive Effect 2. yperconjugation 3. Resonance δ+ 3 C C δ+ δ+ electron donation through σ-bonds toward carbocation delocalizes charge (spreads out) C-C σ-bonds are more polarizable, therefore donate more electron density through σ-bonds 1º carbocation more C-C σ-bonds = more stable carbocation Slide 15 15

16 Review: Carbocation Stability 1. Inductive Effect 2. yperconjugation 3. Resonance δ+ 3 C C δ+ δ+ electron donation through σ-bonds toward carbocation delocalizes charge (spreads out) C-C σ-bonds are more polarizable, therefore donate more electron density through σ-bonds 2º carbocation more C-C σ-bonds = more stable carbocation Slide 16 16

17 Review: Carbocation Stability 1. Inductive Effect 2. yperconjugation 3. Resonance δ+ 3 C C δ+ δ+ electron donation through σ-bonds toward carbocation delocalizes charge (spreads out) C-C σ-bonds are more polarizable, therefore donate more electron density through σ-bonds 3º carbocation more C-C σ-bonds = more stable carbocation Slide 17 17

18 Review: Carbocation Stability 1. Inductive Effect 2. yperconjugation 3. Resonance C C 1º carbocation electron donation through σ-bonds toward carbocation delocalizes charge (spreads out) C-C σ-bonds are more polarizable, therefore donate more electron density through s-bonds more C-C σ-bonds = more stable carbocation Slide 18 18

19 Review: Carbocation Stability 1. Inductive Effect 2. yperconjugation 3. Resonance C C 2º carbocation C 2 electron donation through σ-bonds toward carbocation delocalizes charge (spreads out) C-C σ-bonds are more polarizable, therefore donate more electron density through s-bonds more C-C σ-bonds = more stable carbocation Slide 19 19

20 Review: Carbocation Stability 1. Inductive Effect 2. yperconjugation 3. Resonance C C 3º carbocation C 2 C 2 electron donation through σ-bonds toward carbocation delocalizes charge (spreads out) C-C σ-bonds are more polarizable, therefore donate more electron density through s-bonds more C-C σ-bonds = more stable carbocation Slide 20 20

21 Review: Carbocation Stability 1. Inductive Effect 2. yperconjugation 3. Resonance Cl Nuc Nuc no resonance = less stable (higher energy) = slower Cl Nuc Nuc resonance = more stable (lower energy) = faster Slide 21 21

22 Carbocation Stability: Solvent Effect Cl + solvent solvolysis solvent dielectric constant (ɛ) = a crude measure of a solvent s polarity more polar solvent = more stable carbocation = faster reaction (krel) polar stabilizes polar Slide 22 Lecture: 18: March

23 Carbocation Stability: Solvent Effect Cl + acetic acid acetolysis k rel = 1 dielectric constant (e) = a crude measure of a solvent s polarity more polar solvent = more stable carbocation = faster reaction (krel) polar stabilizes polar Slide 23 Lecture: 18: March

24 Carbocation Stability: Solvent Effect Cl + 3 C methanol methanolysis k rel = 4 3 C dielectric constant (e) = a crude measure of a solvent s polarity more polar solvent = more stable carbocation = faster reaction (krel) polar stabilizes polar Slide 24 Lecture: 18: March

25 Carbocation Stability: Solvent Effect Cl + formolysis k rel = 5,000 formic acid dielectric constant (e) = a crude measure of a solvent s polarity more polar solvent = more stable carbocation = faster reaction (krel) polar stabilizes polar Slide 25 Lecture: 18: March

26 Carbocation Stability: Solvent Effect Cl + 2 water hydrolysis k rel = 150,000 dielectric constant (e) = a crude measure of a solvent s polarity more polar solvent = more stable carbocation = faster reaction (krel) polar stabilizes polar Slide 26 Lecture: 18: March

27 Solvent Effect on Carbocation Stability Cl δ δ + Cl δ δ + + Cl + Cl Cl Cl polar solvent reduce charge in TS through dipole-dipole interactions less TS charge = lower energy lower energy TS = faster SN1 little effect on alkyl halide reactant non-polar solvent does not have strong VW interactions more TS charge = higher energy higher energy TS = faster SN1 little effect on alkyl halide reactant Slide 27 27

28 Solvent Effects on SN2 Reactions? Br + NaN 3 N 3 protic: contains an acidic hydrogen capable of -bonding (, N, S) no trend between dielectric constant and rate for SN2 reactions fastest SN2 reactions in polar aprotic (no acidic hydrogen) Slide 28 28

29 Solvent Effects on SN2 Reactions polar protic solvents = more solvation of nucleophile, especially through hydrogen bonding 3 C 3 C C N protic solvent = capable of hydrogen bonding more hydrogen bonding = more solvation of nucleophile form a solvation shell around nucleophile more solvated = decreased nucleophilicity slower SN2 reaction Slide 29 29

30 Solvent Effects on SN2 Reactions polar aprotic solvents = less solvation of nucleophile = more nucleophilic = faster SN2 3 C C N 3 C C N N C N C N C N C N C N C aprotic solvent = not capable of hydrogen bonding less solvation than protic nucleophile is freer less solvated = increased nucleophilicity faster SN2 reaction Slide 30 30

31 Solvent Effects on SN2 Reactions (methanol) Br + NaN 3 20 hours N 3 CN (acetonitrile) Br + NaN 3 20 minutes N 3 Slide 31 31

32 Self-Test Question Determine the fastest reaction in each pair and list them in order of a,b,c. a b c Br Br Cl Br Br Br NaN 3 N 3 DMF NaN 3 N 3 DMF NaS DMS NaS DMS NaCN CN NaCN S S CN CN A. 1,1,1 B. 2,2,1 C. 1,2,2 D. 2,1,1 E. 2,1,2 University of Illinois at Chicago CEM 232, Spring 2010 Slide 32 32

33 Stereochemistry of SN1 Reactions generally, SN1 reactions are not stereospecific nucleophiles can add to both sides of a carbocation intermediate results in inversion of configuration and retention of configuration racemization: conversion of optically active starting material to a racemic mixture (1:1 of enantiomers) Why is racemization not complete in above example? Slide 33 33

34 Stereochemistry of SN1 Reactions Slide 34 34

35 Elimination-Substitution Competition When the nucleophile is anionic, elimination competes with substitution Slide 35 35

36 Elimination-Substitution Competition When the nucleophile is anionic, elimination competes with substitution C 2 Br E2 C 2 Br S N 2 C 2 Anion must be more basic than hydroxide (pka of conjugate acid > 15.7) for E1 or E2 to be a competing mechanism Slide 36 36

37 Elimination-Substitution Competition When the nucleophile is anionic, elimination competes with substitution Br E1 C 2 S N 1 C 2 Br C 2 Anion must be more basic than hydroxide (pka of conjugate acid > 15.7) for E1 or E2 to be a competing mechanism Slide 37 37

38 Conditions Favoring Substitution 1. Low steric hinderance: a. small nucleophiles b. least substituted alkyl halide possible 2.Neutral nucleophiles (like solvolysis) 3.r anionic nucleophiles less basic than Slide 38 38

39 Conditions Favoring Substitution 1. Low steric hinderance: a. small nucleophiles b. least substituted alkyl halide possible 2.Neutral nucleophiles (like solvolysis) 3.r anionic nucleophiles less basic than Slide 39 39

40 Conditions Favoring Substitution 1. Low steric hinderance: a. small nucleophiles b. least substituted alkyl halide possible 2.Neutral nucleophiles (like solvolysis) 3.r anionic nucleophiles less basic than KC(C3)3 is so large that it prefers E2 even when the alkyl halide is primary Slide 40 40

41 Conditions Favoring Substitution 1. Low steric hinderance: a. small nucleophiles b. least substituted alkyl halide possible 2.Neutral nucleophiles (like solvolysis) 3.r anionic nucleophiles less basic than Cl + 3 C methanol methanolysis k rel = 4 3 C Neutral nucleophiles are not basic enough to deprotonate a β- hydrogen in an E2 mechanism; they also undergo addition to carbocations faster than deprotonation in an E1 mechanism Slide 41 41

42 Conditions Favoring Substitution 1. Low steric hinderance: a. small nucleophiles b. least substituted alkyl halide possible 2.Neutral nucleophiles (like solvolysis) 3.r anionic nucleophiles less basic than pka (2) = 15.7 pka (CN) = 9.1 stonger acid = weaker conjugate base Slide 42 42

43 Conditions Favoring Elimination 1. Large steric interactions: a. large nucleophiles b. most substituted alkyl halide possible 2. Anionic nucleophiles more basic than Br + K + C DMS pka (2) = 15.7 pka (tert-butanol) = 18 stonger acid = weaker conjugate base Slide 43 43

44 Self-Test Question What is the major product of the reaction below? A 3 C 3 C C 2 B 3 C 3 C 3 C 3 C Cl + S C N S C N DMF C 3 C 3 C N C S DMF = N,N-dimethylformamide (common polar aprotic solvent) 3 C N D 3 C 3 C S C N University of Illinois at Chicago CEM 232, Spring 2010 Slide 44 44

45 Sulfonic Acids & Sulfonyl Chlorides 3 C S p-toluenesulfonic acid Ts 3 C S methanesulfonic acid Ms F 3 C S trifluoromethanesulfonic acid Tf 3 C S Cl p-toluenesulfonyl chloride TsCl 3 C S Cl methanesulfonyl chloride MsCl F 3 C S Cl trifluoromethanesulfonyl chloride TfCl 3 C toluene R carboxylic acid R Cl acid chloride Slide 45 45

46 Alkyl Sulfonates 3 C S Cl p-toluenesulfonyl chloride TsCl + 3 C S 3 C S Cl methanesulfonyl chloride MsCl + 3 C S F 3 C S Cl trifluoromethanesulfonyl chloride TfCl + You will learn the mechanism for this process in Chapter 20; Don t worry about it for now. F 3 C S Slide 46 46

47 Alkyl Sulfonates Ts Cl + Ts + Cl Ms Cl + Ms + Cl Tf Cl + Tf + Cl Pyridine (Py) is also usually added in this reaction to neutralize the Cl produced N N + Cl Cl You should memorize the abbreviations for these three groups. pyridine pyridinium chloride Slide 47 47

48 Alkyl Sulfonates Are Electrophiles Ts Nuc Nuc + + Ts Ts 3 C S 3 C S 3 C S sulfonates (Ts, Ms, Tf ) are highly stabilized by resonance = very weak conjugate bases = very good leaving group Slide 48 48

49 Alkyl Sulfonates Are Electrophiles Slide 49 49

50 Ts, Ms & Tf are Excellent Leaving Groups 3 C 3 C S S 3 C S C S + + sulfonic acids are very strong acids = conjugate bases very stable (weak): conjugate bases stabilized by resonance and inductive effects = F 3 C S F 3 C S + + that makes sulfonates (conjugate bases) very good leaving groups Slide 50 50

51 Self-Test Question Predict the major organic product of the reaction below. A I B Ms 1. MsCl, Pyridine C Ms 2. NaI, acetone D E University of Illinois at Chicago CEM 232, Spring 2010 Slide 51 51

52 CEM 232 rganic Chemistry I at Chicago Next Lecture... Chapter 9: Sections Quiz Next Week... Chapter 8 52