Essential Organic Chemistry. Chapter 9

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1 Essential Organic Chemistry Paula Yurkanis Bruice Chapter 9 Substitution and Elimination Reactions of Alkyl Halides

2 9.1 How Alkyl Halides React

3 Substitution Reactions One group takes the place of another. Y + R X R Y + X Y takes the place of X (Substitution) Y displaces X

4 Nucleophilic Substitution NUCLEOPHILIC DISPLACEMENT substrate leaving group Nu: - + R X R Nu + :X - nucleophile product The nucleophile displaces the leaving group. This is a substitution reaction: Nu substitutes for X (takes its place).

5 Example 1 H 3 C CH 2 Br + NaI acetone H 3C CH 2 I + NaBr soluble insoluble iodide displaces bromide at carbon

6 DISPLACEMENT REACTIONS NUCLEOPHILIC SUBSTITUTION REACTIONS (substitution at carbon) can be compared to ACID BASE REACTIONS (substitution at hydrogen)

7 COMPARE THESE REACTIONS DISPLACEMENT AT CARBON Nu: - + R X R Nu + :X - nucleophile substrate product leaving group DISPLACEMENT AT HYDROGEN B: - + H X B H + :X - base acid conjugate acid conjugate base

8 THESE REACTIONS FIND WIDE APPLICATION SINCE WE CAN USE A WIDE RANGE OF NUCLEOPHILES

9 NUCLEOPHILES A WIDE SELECTION OF NUCLEOPHILES MAKES POSSIBLE THE SYNTHESIS OF MANY TYPES OF ORGANIC COMPOUNDS: R-Y + Nu Nucleophile R-Nu + Y Product Class Cl -,Br -,I - R X alkyl halides OH - R OH alcohols R'O - R O R' ethers C N - C N O R' C O - R O R' C O R nitriles esters R' C C: - R' C C R alkynes SH - R S H thiols

10 THE NUCLEOPHILE DOES NOT NEED TO BE CHARGED HOWEVER, REACTIVE ATOMS BEAR A LONE PAIR H O H Under some circumstances water will react. + R Br H O H O H R + R O H - + Br H + H 3 O + + Br - Nucleophile Product Class H O H R O R ' NH 3 O H R' O H R alcohols ethers R NH 2 amines R' NH 2 R' NH R amines

11 A Closer Look at Alkyl Halides Carbon and halogens have different electronegativity. Carbon-halogen bonds are polarized. Carbon is thought to be positive end of dipole. Nucleophiles can attack at positively charged carbon. Cl Br l H H H H H H H H H

12 A Closer Look at the Reactions All substitution reactions follow a general scheme RBr + NaOH ROH + NaBr Two reactions follow... From the outcome they look Identical; however, a closer inspection shows they are different!

13 TWO LOOK-ALIKE REACTIONS RBr + NaOH ROH + NaBr 1) 80% ethanol CH 3 Br + NaOH CH 3 OH + Br - 20% water 55 o C 2) rate = k 2 [RBr][NaOH] high conc. NaOH Speed of reaction depends on two concentrations H 3 C CH 3 C Br CH 3 + rate = k 1 [RBr] NaOH 80% ethanol 20% water low conc. NaOH 55 o C H 3 C CH 3 C OH CH 3 + Br - (+ some alkene by E1, E2) Speed of reaction independent of nucleophile concentration

14 Two Different Substitution Reactions We can distinguish two reactions based on their kinetics. First is S N 2, depends on substrate AND nucleophile concentration. Second is S N 1, depends only on substrate concentration.

15 9.2 The Mechanism of An S N 2 Reaction

16 80% ethanol CH 3 Br + NaOH CH 3 OH + Br - 20% water 55 o C rate = k 2 [RBr][NaOH] H O - CH 3 Br 80% ethanol 20% water CH 3 OH + Br - Rate dependence of the reaction is interpreted in a way that we expect a bimolecular reaction with a concerted mechanism S N 2 substitution nucleophilic bimolecular

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18 S N 2 Reaction Rate dependence is 2 nd order Two molecules have to come together to form new bonds Bimolecular reaction

19 Mechanism ENERGY PROFILE E N E R G Y HO - Br Br -

20 Mechanism ENERGY PROFILE E N E R G Y HO - HO - Br Br -

21 Mechanism ENERGY PROFILE E N E R G Y HO - HO - Br Br -

22 Mechanism ENERGY PROFILE E N E R G Y HO - HO - Br Br -

23 Mechanism ENERGY PROFILE E N E R G Y HO - HO Br Br -

24 Mechanism ENERGY PROFILE HO - HO Br -- Br - E N E R G Y

25 Mechanism ENERGY PROFILE HO - HO Br - Br - E N E R G Y

26 Stereochemistry Old bond is broken simultaneously with the new bond formed. Well-defined outcome Stereochemistry is inverted

27 Steric effects Factors Affecting S N 2 Approaching the polarized carbon gets more and more difficult.

28 S N 2 Energy Profile of S N 2

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32 9.3 Factors that Affect S N 2 Reactions Leaving Group I > Br > Cl > F The lower the basicity, the better the leaving group. Nucleophile HO > H 2 O; CH 3 O > CH 3 OH The better the base, the better the nucleophile NH 2 > HO > F

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38 9.4 The Mechanism of An S N 1 Reaction

39 S N 1 H 3 C CH 3 C Br + NaOH 80% ethanol 20% water 55 o C H 3 C CH 3 C OH + Br - CH 3 CH 3 rate = k 1 [RBr] Rate depends only on substrate concentration. Two independent steps that differ significantly in speed. Unimolecular S N 1 substitution nucleophilic unimolecular

40 S N 1 H 3 C CH 3 C Br + CH 3 CH 3 OH 80% ethanol NaOH H C + Br - 20% water 3 C CH 3 slow H 3 C O H CH 3 C+ + Br - CH 3 fast Assuming the formation of a carbocation intermediate as the rate-determining step, explains speed of reaction

41 S N 1 Reaction profile CH 3 Br - Br CH 3 CH 3 - OH

42 S N 1 Reaction profile CH 3 Br - Br CH 3 CH 3 - OH Bond gets longer

43 S N 1 Reaction profile CH 3 Br - Br CH 3 CH 3 - OH Bond gets longer and longer Rehybridization sp 3 sp 2

44 S N 1 Reaction profile Br - CH 3 CH 3 CH 3 - OH Bond gets longer and longer Rehybridization sp 3 sp 2

45 S N 1 Reaction profile Br - CH 3 CH 3 CH 3 Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed - OH

46 S N 1 Reaction profile Br - CH 3 CH 3 CH 3 - OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place

47 S N 1 Reaction profile Br - CH 3 CH 3 CH 3 OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place

48 S N 1 Reaction profile Br - CH 3 CH 3 CH 3 OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place Bond forms

49 S N 1 Reaction profile Br - CH 3 CH 3 CH 3 OH - OH Bond gets longer and longer Rehybridization sp 3 sp 2 sp 2 -Hybridized intermediate formed Nucleophile approaches Rehybridization sp 3 sp 2 takes place Bond forms

50 Energy Profile of S N 1 E N E R G Y transition state activation energy 1 carbocation intermediate 1 2 S N 1 transition state 2 activation energy 2 starting material step 1 step 2 DH REACTION COORDINATE product

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53 S N 1 Rate dependence is 1 st order Rate depends only on formation of cation Unimolecular reaction The intermediate requires rehybridization sp 3 sp 2

54 Stereochemistry First, old bond is broken. In a second step, we form new bond. We have a carbocation intermediate. This requires rehybridization sp 3 sp 2 Stereochemical information is lost. Racemate formed. Br HO - OH + OH

55 9.5 Factors that Affect S N 1 Reactions Cation stability 3 o alkyl halide > 2 o alkyl halide > 1 o alkyl halide. Leaving group The weaker the bond, the easier to break. RI > RBr > RCl > RF Nucleophile NO EFFECT.

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60 9.6 Comparing S N 2 and S N 1 Reactions

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63 9.7 Elimination Reactions of Alkyl Halides In an elimination reaction the starting material loses the elements of a small molecule such as HCl or HBr during the course of the reaction to form the product. C H C X -HX

64 Example Alkyl halide + strong base and heat LOSS OF HCl H 3 CH 2 CH 2 CH 2 C Cl NaOH D H 3 CH 2 CCH CH 2 H 3 CH 2 CH 2 CHCH 3 Cl NaOH D H 3 CCH CH 2 CH 3

65 Elimination In this case the nucleophile reacts as a base; we observe elimination reactions. A hydrogen is removed from a carbon atom. The halogen is removed from the adjacent carbon. Note that the elimination reaction is the reverse of an addition reaction.

66 E2 Reaction THE REACTION IS A b-elimination The b-hydrogen is attached to the b-carbon. H C C a-carbon b-carbon Cl The functional group is attached to the a-carbon. Since the b-hydrogen is lost this reaction is called a b-elimination.

67 Mechanism of E2 THE BASE TAKES THE b-hydrogen B: H B H C C Cl :.. : C C.. : Cl.. : Bond formation (p bond) and breaking bonds (C-H and C-X s bond) take place simultaneously

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69 Regioselectivity WHAT HAPPENS IF THERE IS MORE THAN ONE b-hydrogen? b b H H C C Br a C

70 Regioselectivity b b Major product - b-h H 3 C CH CH CH 3 H H H H 2-butene H C C C C H H H Br H H 3 C CH 2 CH CH 2 2-bromobutane 1-butene Major product is the one with lowest energy Minor product b -H

71 Regioselectivity In some cases we have more than two b-hydrogens b b CH 3 Cl NaOCH 3 CH 3 OH/ D b`` 1-methylcyclohexene Major product - b-h Minor product b -H methylenecyclohexane b = b 1-methylcyclohexene

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75 E1 ALKYL HALIDES + WEAK BASE (SOLVOLYSIS) The removal of a b-hydrogen becomes difficult without a strong base and a different mechanism (ionization) begins to take place if the substrate is capable.

76 The E1 Elimination Reaction (two steps) H C unimolecular C X rate = k[rx] weak base slow step one B: H C step two C carbocation C + fast C + :X 3 o > 2 o > 1 o also favored if a resonancestabilized carbocation is formed Works best in a polar solvent. IONS FORMED

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78 E N E R G Y ENERGY PROFILE two-step reaction TS 1 Ea 1 carbocation intermediate Ea 2 TS 2 E1 starting material step 1 step 2 slow DH product

79 Regioselectivity H 3 C CH 3 E1 H 3 C H 3 C CH 3 H 3 C Cl major CH 3 + CH 3 minor CH 2 Major products in E1 eliminations are the alkenes that are thermodynamically most stable.

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87 9.9 Competition Between S N 2/E2 and S N 1/E1 Consider concentration and reactivity S N 2/E2 are favored by a high concentration of a good nucleophile/strong base. S N 1/E1 are favored by a poor nucleophile/ weak base.

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92 9.10 Competition Between Substitution and Elimination

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