8Chapter 08

8Chapter 08 - Chapter 8 Nucleophilic Substitution Dr....

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Chapter 8 Nucleophilic Substitution Dr. Wolf's CHM 201 & 202 8-1 8.1 Functional Group Functional Transformation By Nucleophilic Substitution Substitution Dr. Wolf's CHM 201 & 202 8-2 Nucleophilic Substitution Nucleophilic Substitution – Y: + R X Y – R +: X nucleophile is a Lewis base (electron-pair donor) often negatively charged and used as often Na+ or K+ salt Na substrate is usually an alkyl halide substrate alkyl halide Dr. Wolf's CHM 201 & 202 8-3 Nucleophilic Substitution Nucleophilic Substitution Substrate cannot be an a vinylic halide or an aryl halide, except under certain conditions to be discussed in Chapter 12. X C Dr. Wolf's CHM 201 & 202 C X 8-4 Table 8.1 Examples of Nucleophilic Substitution Table 8.1 Examples of Nucleophilic Substitution Alkoxide ion as the nucleophile R' – .. O: .. + R X gives an ether R' Dr. Wolf's CHM 201 & 202 .. O .. R + – :X 8-5 Example Example (CH3)2CHCH2ONa + CH3CH2Br Isobutyl alcohol (CH3)2CHCH2OCH2CH3 + NaBr Ethyl isobutyl ether (66%) Dr. Wolf's CHM 201 & 202 8-6 Table 8.1 Examples of Nucleophilic Substitution Table 8.1 Examples of Nucleophilic Substitution Carboxylate ion as the nucleophile O – .. + R X R'C O: .. gives an ester O R'C Dr. Wolf's CHM 201 & 202 .. O .. R + – :X 8-7 Example Example O CH3(CH2)16C OK + CH3CH2I acetone, water O CH3(CH2)16C O CH2CH3 + KI Ethyl octadecanoate (95%) Dr. Wolf's CHM 201 & 202 8-8 Table 8.1 Examples of Nucleophilic Substitution Table 8.1 Examples of Nucleophilic Substitution Hydrogen sulfide ion as the nucleophile H – .. S: .. H .. S .. + R X gives a thiol Dr. Wolf's CHM 201 & 202 R + – :X 8-9 Example Example KSH + CH3CH(CH2)6CH3 Br ethanol, water CH3CH(CH2)6CH3 + KBr KBr SH 2-Nonanethiol (74%) Dr. Wolf's CHM 201 & 202 8-10 Table 8.1 Examples of Nucleophilic Substitution Table 8.1 Examples of Nucleophilic Substitution Cyanide ion as the nucleophile :N – C: + R X gives a nitrile :N Dr. Wolf's CHM 201 & 202 C R + – :X 8-11 Example Example NaCN + NaCN Br DMSO DMSO CN + NaBr NaBr Cyclopentyl cyanide (70%) Dr. Wolf's CHM 201 & 202 8-12 Table 8.1 Examples of Nucleophilic Substitution Table 8.1 Examples of Nucleophilic Substitution Azide ion as the nucleophile – :N .. + N – N: .. gives an alkyl azide + – :N N N .. .. Dr. Wolf's CHM 201 & 202 + R R + X – :X 8-13 Example Example NaN3 + CH3CH2CH2CH2CH2I 2-Propanol-water CH3CH2CH2CH2CH2N3 + NaI Pentyl azide (52%) Dr. Wolf's CHM 201 & 202 8-14 Table 8.1 Examples of Nucleophilic Substitution Table 8.1 Examples of Nucleophilic Substitution Iodide ion as the nucleophile – .. : ..: I + gives an alkyl iodide .. : .. R I Dr. Wolf's CHM 201 & 202 R + X – :X 8-15 Example Example CH3CHCH3 + NaI Br acetone CH3CHCH3 + NaBr I Dr. Wolf's CHM 201 & 202 63% NaI is soluble in acetone; NaI NaCl and NaBr are not soluble in acetone. soluble 8-16 8.2 Relative Reactivity of Halide Relative Leaving Groups Leaving Dr. Wolf's CHM 201 & 202 8-17 Generalization •Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination. RI most reactive RBr RCl RF Dr. Wolf's CHM 201 & 202 least reactive 8-18 Problem 8.2 Problem 8.2 Problem A single organic product was obtained when single 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? aqueous BrCH2CH2CH2Cl + NaCN Br Br is a better leaving group than Cl Dr. Wolf's CHM 201 & 202 8-19 Problem 8.2 Problem 8.2 Problem A single organic product was obtained when single 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product? aqueous BrCH2CH2CH2Cl + NaCN Br :N Dr. Wolf's CHM 201 & 202 C CH2CH2CH2Cl + NaBr 8-20 8.3 The SN2 Mechanism of Nucleophilic Substitution Dr. Wolf's CHM 201 & 202 8-21 Kinetics •Many nucleophilic substitutions follow a second-order rate law. CH3Br + HO – → CH3OH + Br – • rate = k[CH3Br][HO – ] • inference: rate-determining step is bimolecular Dr. Wolf's CHM 201 & 202 8-22 Bimolecular mechanism δ− HO δ− Br CH3 transition state HO – + CH3Br Dr. Wolf's CHM 201 & 202 •one step HOCH3 + Br – 8-23 Stereochemistry •Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration. Dr. Wolf's CHM 201 & 202 8-24 Inversion of Configuration nucleophile attacks carbon from side opposite bond to the leaving group Dr. Wolf's CHM 201 & 202 three-dimensional arrangement of bonds in product is opposite to product that of reactant that 8-25 Stereospecific Reaction •A stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products. •The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. • (+)-2-Bromooctane → (–)-2-Octanol • (–)-2-Bromooctane → (+)-2-Octanol Dr. Wolf's CHM 201 & 202 8-26 Stereospecific Reaction CH3(CH2)5 H (CH ) CH 25 3 H C Br CH3 (S)-(+)-2-Bromooctane Dr. Wolf's CHM 201 & 202 NaOH HO C CH3 (R)-(–)-2-Octanol 8-27 Problem 8.4 The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the(–)-2-octanol formed from it by nucleophilic substitution with inversion of CH3 CH3 configuration. H Br CH2(CH2)4CH3 Dr. Wolf's CHM 201 & 202 HO H CH2(CH2)4CH3 8-28 8.4 Steric Effects in SN2 Reactions Dr. Wolf's CHM 201 & 202 8-29 Crowding at the Reaction Site The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects. Crowding at the carbon that bears Crowding the leaving group slows the rate of the bimolecular nucleophilic substitution. Dr. Wolf's CHM 201 & 202 8-30 Table 8.2 Reactivity toward substitution by the SN2 mechanism RBr + LiI → RI + LiBr RBr •Alkyl bromide Class Relative rate •CH3Br Methyl 221,000 •CH3CH2Br Primary 1,350 •(CH3)2CHBr Secondary 1 •(CH ) CBr too small Dr. Wolf's CHM 2013 3 & 202 Tertiary 8-31 Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr Dr. Wolf's CHM 201 & 202 8-32 Decreasing SN2 Reactivity CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr Dr. Wolf's CHM 201 & 202 8-33 Crowding Adjacent to the Reaction Site The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects. Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the nucleophilic effect is smaller. effect Dr. Wolf's CHM 201 & 202 8-34 Table 8.3 Effect of chain branching on rate of SN2 substitution+ LiBr RBr + LiI → RI RBr •Alkyl bromide Structure Relative rate •Ethyl CH3CH2Br 1.0 •Propyl CH3CH2CH2Br 0.8 •Isobutyl (CH3)2CHCH2Br 0.036 •Neopentyl (CH3)3CCH2Br Dr. Wolf's CHM 201 & 202 0.00002 8-35 8.5 Nucleophiles and Nucleophilicity Dr. Wolf's CHM 201 & 202 8-36 Nucleophiles Nucleophiles The nucleophiles described in Sections 8.1-8.6 have been anions. – .. – .. – .. – : N C: etc. HS: HO: CH3O : .. .. .. Not all nucleophiles are anions. Many are neutral. .. .. : NH3 for example CH3OH HOH .. .. All nucleophiles, however, are Lewis bases. Dr. Wolf's CHM 201 & 202 8-37 Nucleophiles Nucleophiles Many of the solvents in which nucleophilic Many substitutions are carried out are themselves substitutions nucleophiles. .. HOH .. .. CH3OH .. for example The term ssolvolysisrefers to a nucleophilic The term olvolysis rrefers to a nucleophilic efers The The refers substitution in which the nucleophile is the solvent. substitution in which the nucleophile is the solvent. Dr. Wolf's CHM 201 & 202 8-38 Solvolysis Solvolysis substitution by an anionic nucleophile R—X + :Nu— R—X R—Nu + :X— R—Nu solvolysis R—X + :Nu—H R—X + R—Nu—H + :X— —Nu—H step in which nucleophilic substitution occurs Dr. Wolf's CHM 201 & 202 8-39 Solvolysis Solvolysis substitution by an anionic nucleophile R—X + :Nu— R—X R—Nu + :X— R—Nu solvolysis R—X + :Nu—H R—X + RNu—H + :X— —Nu—H products of overall reaction R—Nu + HX —Nu Dr. Wolf's CHM 201 & 202 8-40 Example: Methanolysis Example: Methanolysis Methanolysis is a nucleophilic substitution in Methanolysis which methanol acts as both the solvent and which the nucleophile. CH3 R—X + : O: + R O: H H Dr. Wolf's CHM 201 & 202 CH3 CH3 –H+ R O: .. The product The is a methyl ether. ether. 8-41 Typical solvents in solvolysis Typical solvents in solvolysis solvent product from RX water (HOH) methanol (CH3OH) ethanol (CH3CH2OH) ROH ROCH3 ROCH2CH3 O O formic acid (HCOH) O acetic acid (CH3COH) Dr. Wolf's CHM 201 & 202 ROCH O ROCCH3 8-42 Nucleophilicity is a measure Nucleophilicity is a measure of the reactivity of a nucleophile. of the reactivity of a nucleophile. • Table 8.4 compares the relative rates of Table nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relative methanol, rate of 1.0. Dr. Wolf's CHM 201 & 202 8-43 Table 8.4 Nucleophilicity Rank Rank Nucleophile Nucleophile strong sstrong trong strong ggood ood good good II,-,HS-,-,RS- HS RS Br-r,-,HO-,-, Br HO Br B RO-,-,CN-,-,N3- RO CN N3 NH3, ,Cl-,-,F-,-,RCO2- NH3 Cl F RCO2 H2O, ROH H2O, ROH RCO2H RCO2H fair fair weak weak very weak very weak Dr. Wolf's CHM 201 & 202 2 Relative Relative rrate ate rate rate >1055 >10 1004 104 10 1 1033 10 1 1 10-2-2 10 8-44 Major factors that control nucleophilicity Major factors that control nucleophilicity 1) basicity 2) solvation small negative ions are highly small solvated in protic solvents solvated large negative ions are less solvated 3) polarizability Dr. Wolf's CHM 201 & 202 8-45 Table 8.4 Nucleophilicity Rank Rank Nucleophile Nucleophile Relative Relative rrate ate rate rate good good HO––,RO–– HO , RO HO HO 1044 10 RCO2–– RCO2 1033 10 H2O, ROH H2O, ROH 1 1 fair fair weak weak When the attacking atom is the same (oxygen iin this case), nucleophilicity increases with n increasing basicity. increasing Dr. Wolf's CHM 201 & 202 8-46 Major factors that control nucleophilicity Major factors that control nucleophilicity 1) basicity 2) solvation small negative ions are highly small solvated in protic solvents solvated large negative ions are less solvated 3) polarizability Dr. Wolf's CHM 201 & 202 8-47 Table 8.4 Nucleophilicity Rank Rank Nucleophile Nucleophile Relative Relative rate rate strong strong II- >1055 >10 ggood ood good good Br-rBr Br B 1044 10 fair fair Cl-,-,F- Cl F 1033 10 A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic. Dr. Wolf's CHM 201 & 202 8-48 Major factors that control nucleophilicity Major factors that control nucleophilicity 1) basicity 2) solvation small negative ions are highly small solvated in protic solvents solvated large negative ions are less solvated 3) polarizability Dr. Wolf's CHM 201 & 202 8-49 Table 8.4 Nucleophilicity Rank Rank Nucleophile Nucleophile Relative Relative rreactivity eactivity reactivity reactivity strong sstrong trong strong II- >1055 >10 ggood ood good good Br-rBr Br B 1044 10 fair fair Cl-,-,F- Cl F 1033 10 More polarizable ions are more nucleophilic than lless polarizable ones. Polarizability increases ess with increasing ionic size. with Dr. Wolf's CHM 201 & 202 8-50 8.6 Unimolecular Nucleophilic Unimolecular Substitution SN1 Dr. Wolf's CHM 201 & 202 8-51 Tertiary alkyl halides are very unreactive in Tertiary alkyl halides are very unreactive in Tertiary Tertiary substitutions that proceed by the SN2 mechanism. ssubstitutions that proceed by the S 2 mechanism. ubstitutions substitutions N But they do undergo nucleophilic But substitution. But by a mechanism different from SN2. But 2. The most common examples are seen in solvolysis reactions. solvolysis Dr. Wolf's CHM 201 & 202 8-52 Example of a solvolysis: Hydrolysis of tert-butyl bromide Example of a solvolysis: Hydrolysis ofttert-butyl bromide ert Example Example tert CH3 CH3 C .. Br : .. H + : O: H CH3 CH3 CH3 C .. OH .. + H .. Br : .. CH3 Dr. Wolf's CHM 201 & 202 8-53 Example of a solvolysis: Hydrolysis of tert-butyl bromide Example of a solvolysis: Hydrolysis ofttert-butyl bromide ert Example Example tert CH3 CH3 C .. Br : .. H + CH3 : O: + H O: C H CH3 CH3 H CH3 + CH3 CH3 C .. OH .. + H .. Br : .. .. – : Br : .. CH3 Dr. Wolf's CHM 201 & 202 8-54 Example of a solvolysis: Hydrolysis of tert-butyl bromide Example of a solvolysis: Hydrolysis ofttert-butyl bromide ert Example Example tert CH3 CH3 C .. Br : .. CH3 H + : O: CH3 CH3 + O: C H H H CH3 + This is the nucleophilic substitution stage of the reaction; the one with which we are concerned. Dr. Wolf's CHM 201 & 202 .. – : Br : .. 8-55 Example of a solvolysis: Hydrolysis of tert-butyl bromide Example of a solvolysis: Hydrolysis ofttert-butyl bromide ert Example Example tert CH3 CH3 C .. Br : .. CH3 H + : O: CH3 CH3 + O: C H H H CH3 + The reaction rate is independent of the concentration of the nucleophile and follows a first-order rate law. rate = k[(CH3)3CBr] rate Dr. Wolf's CHM 201 & 202 .. – : Br : .. 8-56 Example of a solvolysis: Hydrolysis of tert-butyl bromide Example of a solvolysis: Hydrolysis ofttert-butyl bromide ert Example Example tert CH3 CH3 C .. Br : .. CH3 H + : O: CH3 CH3 + O: C H H H CH3 + The mechanism of this step is not SN2. It is called SN1 and and begins with ionization of (CH3)3CBr. begins Dr. Wolf's CHM 201 & 202 .. – : Br : .. 8-57 rrate= kk[alkylhalide] ate rate = [alkyl halide] rate First-order kinetics implies a unimolecular First-order kinetics implies a unimolecular rate-determining step. rate-determining step. Proposed mechanism is called SN1, which stands 1, for for substitution nucleophilic unimolecular Dr. Wolf's CHM 201 & 202 8-58 CH3 CH3 .. Br : .. C CH3 unimolecular unimolecular slow slow H3C + C CH3 + .. – : Br : .. CH3 Dr. Wolf's CHM 201 & 202 8-59 H3C CH3 + C H : O: CH3 H bimolecular bimolecular fast fast CH3 CH3 C CH3 Dr. Wolf's CHM 201 & 202 + H O: H 8-60 carbocation carbocation formation formation carbocation carbocation capture capture R+ proton proton transfer transfer RX + ROH2 Dr. Wolf's CHM 201 & 202 ROH 8-61 Characteristics of the SN1 mechanism first order kinetics: rate = k[RX] unimolecular rate-determining step carbocation intermediate rate follows carbocation stability rearrangements sometimes observed reaction is not stereospecific much racemization in reactions of much optically active alkyl halides optically Dr. Wolf's CHM 201 & 202 8-62 The rate of nucleophilic substitution The rate of nucleophilic substitution by the SN1 mechanism is governed by the SN1 mechanism is governed by electronic effects. by electronic effects. Carbocation formation is rate-determining. Carbocation formation is rate-determining. The more stable the carbocation, the faster The more stable the carbocation, the faster iits rate of formation, and the greater the ts rate of formation, and the greater the iits ts rate of unimolecular nucleophilic substitution. rrate of unimolecular nucleophilic substitution. ate rate Dr. Wolf's CHM 201 & 202 8-63 Table 8.5 Reactivity toward substitution Table 8.5 Reactivity toward substitution by the SN1 mechanism by the SN1 mechanism RBr solvolysis in aqueous formic acid Alkyl bromide Class Relative rate CH3Br Methyl 1 CH3CH2Br Primary 2 (CH3)2CHBr Secondary (CH3)3CBr Tertiary Dr. Wolf's CHM 201 & 202 43 100,000,000 8-64 Decreasing SN1 reactivity Decreasing SN1 reactivity (CH3)3CBr (CH3)2CHBr CH3CH2Br Dr. Wolf's CHM 201 & 202 CH3Br 8-65 8.8 Stereochemistry of SN1 Reactions Dr. Wolf's CHM 201 & 202 8-66 Nucleophilic substitutions that exhibit Nucleophilic substitutions that exhibit first-order kinetic behavior are first-order kinetic behavior are first-order first-order not stereospecific. not stereospecific. not not Dr. Wolf's CHM 201 & 202 8-67 Stereochemistry of an SN1 Reaction Stereochemistry of an SN1 Reaction CH3 H C R-(–)-2-Bromooctane Br CH3(CH2)5 H HO CH3 C (CH2)5CH3 (S)-(+)-2-Octanol (83%) Dr. Wolf's CHM 201 & 202 CH3 H2O H C OH CH3(CH2)5 (R)-(–)-2-Octanol (17%) 8-68 Figure 8.8 Figure 8.8 + Ionization step gives carbocation; three bonds to stereogenic center become coplanar – Dr. Wolf's CHM 201 & 202 8-69 Figure 8.8 Figure 8.8 + – Dr. Wolf's CHM 201 & 202 Leaving group shields one face of carbocation; nucleophile attacks nucleophile faster at opposite face. faster 8-70 Figure 8.8 Figure 8.8 – + – – More than 50% Less than 50% Dr. Wolf's CHM 201 & 202 8-71 8.11 Carbocation Rearrangements in Carbocation SN1 Reactions Dr. Wolf's CHM 201 & 202 8-72 Because carbocations are intermediates Because carbocations are intermediates in SN1 reactions, rearrangements in SN1 reactions, rearrangements are possible. are possible. Dr. Wolf's CHM 201 & 202 8-73 Example Example CH3 C CHCH3 H CH3 Br Dr. Wolf's CHM 201 & 202 CH3 H2O CH3 C OH CH2CH3 (93%) 8-74 Example Example CH3 CH3 C CHCH3 H CH3 Br CH3 CH2CH3 C OH (93%) H2O CH3 CH3 C H Dr. Wolf's CHM 201 & 202 CH3 CHCH3 + CH3 C + CHCH3 H 8-75 8.10 Solvent Effects Dr. Wolf's CHM 201 & 202 8-76 SN1 Reaction Rates Increase SN1Reaction Rates Increase Reaction Reaction innPolar Solvents iin Polar Solvents n i Dr. Wolf's CHM 201 & 202 8-77 Table 8.6 SN1 Reactivity versus Solvent Polarity Solvent Dielectric constant acetic acid methanol formic acid water Relative rate 6 33 58 78 1 4 5,000 150,000 Most polar Most Dr. Wolf's CHM 201 & 202 Fastest rate 8-78 transition transition state stabilized by polar solvent polar δ+ R δ− X δ− R+ energy of RX energy not much affected by RX polarity of solvent solvent Dr. Wolf's CHM 201 & 202 8-79 transition transition state stabilized by polar solvent polar δ+ aactivationenergy ctivation activation energy activation decreases; decreases; decreases; decreases; rate increases rate increases δ− R X δ− R+ energy of RX energy not much affected by polarity of RX solvent solvent Dr. Wolf's CHM 201 & 202 8-80 SN2 Reaction Rates Increase in SN2 Reaction Rates Increase in Polar Aprotic Solvents Polar Aprotic Solvents An aprotic solvent is one that does not have an —OH group. So it does not solvate anion well allowing it to be effective nucleophile allowing Dr. Wolf's CHM 201 & 202 8-81 Table 8.7 Table 8.7 SN2 Reactivity versus Type Solvent TableReactivityReactivity vs of Solvent SN2 8.7 SN2 versus Type of Solvent N CH3CH2CH2CH2Br + N3– Solvent Type CH3OH polar protic H2 O polar protic 7 DMSO DMF polar aprotic polar aprotic 1300 2800 Acetonitrile polar aprotic 5000 Dr. Wolf's CHM 201 & 202 Relative Relative rate rate 1 8-82 Mechanism Summary Mechanism Summary SN1 and SN2 SN1 and SN2 Dr. Wolf's CHM 201 & 202 8-83 When.. . primary alkyl halides undergo nucleophilic substitution, they always react by the SN2 always mechanism mechanism tertiary alkyl halides undergo nucleophilic substitution, they always react by the SN1 always mechanism mechanism secondary alkyl halides undergo nucleophilic substitution, they react by the substitution, SN1 mechanism in the presence of a weak nucleophile (solvolysis) nucleophile SN2 mechanism in the presence of a good Dr. Wolf's CHM 201 & 202 8-84 8.11 Substitution And Elimination Substitution As Competing Reactions As Dr. Wolf's CHM 201 & 202 8-85 We have seen that alkyl halides can react with Lewis We have seen that alkyl halides can react with Lewis bases in two different ways. They can undergo bases in two different ways. They can undergo nucleophilic substitution or elimination. nucleophilic substitution or elimination. β-elimination C H C C + :Y X Dr. Wolf's CHM 201 & 202 C + H Y + :X – – H C C + :X – Y nucleophilic substitution 8-86 How can we tell which reaction pathway is followed How can we tell which reaction pathway is followed for aaparticular alkyl halide? for particular alkyl halide? β-elimination C H C C + :Y X Dr. Wolf's CHM 201 & 202 C + H Y + :X – – H C C + :X – Y nucleophilic substitution 8-87 A systematic approach is to choose as a reference A systematic approach is to choose as a reference point the reaction followed by a typical alkyl halide point the reaction followed by a typical alkyl halide (secondary) with a typical Lewis base (an alkoxide (secondary) with a typical Lewis base (an alkoxide ion). ion). The major reaction of a secondary alkyl halide with an alkoxide ion is with elimination by the E2 mechanism. elimination Dr. Wolf's CHM 201 & 202 8-88 Example Example CH3CHCH3 Br NaOCH2CH3 ethanol, 55°C CH3CHCH3 OCH2CH3 (13%) Dr. Wolf's CHM 201 & 202 + CH3CH=CH2 (87%) 8-89 Figure 8.11 Figure 8.11 Figure E2 CH3CH2 Dr. Wolf's CHM 201 & 202 .. O: .. – Br 8-90 Figure 8.11 Figure 8.11 SN2 CH3CH2 Dr. Wolf's CHM 201 & 202 – .. O: .. Br 8-91 Given that the major reaction of a secondary Given that the major reaction of a secondary aalkylhalide with an alkoxide ion is elimination lkyl alkyl halide with an alkoxide ion is elimination alkyl byythe E2 mechanism, we can expect the b the E2 mechanism, we can expect the proportion of substitution to increase with: ubstitution proportion ofssubstitution to increase with: substitution 1) decreased crowding at the carbon that bears the leaving group Dr. Wolf's CHM 201 & 202 8-92 Decreased crowding at carbon that bears the Decreased crowding at carbon that bears the Decreased Decreased leaving group increases substitution rrelative leaving group increases substitution elative tooelimination. tto elimination. o t primary alkyl halide CH3CH2CH2Br NaOCH2CH3 ethanol, 55°C CH3CH2CH2OCH2CH3 + CH3CH=CH2 (91%) Dr. Wolf's CHM 201 & 202 (9%) 8-93 But a crowded alkoxide base can favor But a crowded alkoxide base can favor But But elimination even with a primary alkyl halide. elimination even with a primary alkyl halide. elimination elimination primary alkyl halide + bulky primary base base CH3(CH2)15CH2CH2Br KOC(CH3)3 tert-butyl alcohol, 40°C CH3(CH2)15CH2CH2OC(CH3)3 (13%) Dr. Wolf's CHM 201 & 202 + CH3(CH2)15CH=CH2 (87%) 8-94 Given that the major reaction of a secondary Given that the major reaction of a secondary aalkylhalide with an alkoxide ion is elimination lkyl alkyl halide with an alkoxide ion is elimination alkyl byythe E2 mechanism, we can expect the b the E2 mechanism, we can expect the proportion of substitution to increase with: ubstitution proportion ofssubstitution to increase with: substitution 1) decreased crowding at the carbon that bears the leaving group 2) decreased basicity of nucleophile Dr. Wolf's CHM 201 & 202 8-95 Weakly basic nucleophile increases Weakly basic nucleophile increases Weakly Weakly substitution rrelativeto elimination ssubstitution elative to elimination ubstitution substitution secondary alkyl halide + weakly basic nucleophile CH3CH(CH2)5CH3 Cl SN2 KCN pKa ((HCN)= 9.1 pKa HCN) = 9.1 DMSO CH3CH(CH2)5CH3 CN (70%) Dr. Wolf's CHM 201 & 202 8-96 Weakly basic nucleophile increases Weakly basic nucleophile increases Weakly Weakly substitution rrelativeto elimination ssubstitution elative to elimination ubstitution substitution secondary alkyl halide + weakly basic nucleophile I SN2 pKa ((HN))= 4.6 pKa HN33 = 4.6 NaN3 (even weaker base) N3 Dr. Wolf's CHM 201 & 202 (75%) 8-97 Tertiary alkyl halides are so sterically hindered Tertiary alkyl halides are so sterically hindered that elimination is the major reaction with all that elimination is the major reaction with all anionic nucleophiles. Only in solvolysis reactions anionic nucleophiles. Only in solvolysis reactions does substitution predominate over elimination does substitution predominate over elimination with tertiary alkyl halides. with tertiary alkyl halides. Dr. Wolf's CHM 201 & 202 8-98 (CH3)2CCH2CH3 Example Example Br CH3 CH3CCH2CH3 CH3 CH3 + CH2=CCH2CH3 + CH3C=CHCH3 OCH2CH3 ethanol, 25°C 36% 64% 2M sodium ethoxide in ethanol, 25°C 1% 99% Dr. Wolf's CHM 201 & 202 8-99 Mechanism Summary Mechanism Summary SN11and SN22and E1 and E2 S and S and E1 and E2 N N Under 2nd order conditions….. STRONG base/nucleophile eg. -OH, -OR ELIMINATION favored with 30 , 20, (and 10 with bulky base eg. -OtBu) SUBSTITUTION favored with 10 (aprotic solvent helps) With WEAK base but good nucleophile e.g. -CN, -N3 Or Under 1st order conditions….. WEAK base/nucleophile (solvolysis) e.g. H2O, ROH, SUBSTITUTION favored (increased solvent polarity helps) Dr. Wolf's CHM 201 & 202 8-100 8.12 Nucleophilic Substitution of Alkyl Sulfonates Dr. Wolf's CHM 201 & 202 8-101 Leaving Groups Leaving Groups • we have seen numerous examples of nucleophilic substitution in which X in RX is a halogen • halogen is not the only possible leaving group though Dr. Wolf's CHM 201 & 202 8-102 Other RX compounds Other RX compounds O HOSOH ROSCH3 O O O O Sulfuric acid ROS Alkyl methanesulfonate (mesylate) CH3 CH O Alkyl p-toluenesulfonate (tosylate) • undergo same kinds of reactions as alkyl halides Dr. Wolf's CHM 201 & 202 8-103 Preparation Preparation Tosylates are prepared by the reaction of Tosylates alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine) ROH + CH3 CH SO2Cl pyridine O ROS CH3 CH • (abbreviated as ROTs) O Dr. Wolf's CHM 201 & 202 8-104 Tosylates undergo typical Tosylates undergo typical nucleophilic substitution nucleophilic substitution rreactions eactions H KCN H CH2OTs ethanolwater CH2CN (86%) SN2 Dr. Wolf's CHM 201 & 202 8-105 •The best leaving groups are weakly basic Dr. Wolf's CHM 201 & 202 8-106 Table 8.8 Table 8.8 Approximate Relative Reactivity of Approximate Relative Reactivity of Leaving Groups Leaving Groups •Leaving GroupRelative Conjugate acid Ka of Rate of leaving group conj. acid • F– 10-5 HF 3.5 x 10-4 wk acid • Cl– 1 HCl 107 • Br– 10 HBr 109 • I– 102 HI 1010 H2O 101 H3O+ 56 • • TsO– • CF3SO2O– Dr. Wolf's CHM 201 & 202 105 108 TsOH CF3SO2OH 600 106 8-107 Table 8.8 Table 8.8 Approximate Relative Reactivity of Approximate Relative Reactivity of Leaving Groups Leaving Groups •Leaving GroupRelative Conjugate acid Ka of Rate of leaving group conj. acid • F– 10-5 HF 3.5 x 10-4 • Cl– esters are extremely good leaving groups; 1 HCl 107 Sulfonate • ulfonate ions are very weak bases. Br– 10 HBr 109 s • I– 102 HI 1010 H2O 101 H3O+ 56 • • TsO– • CF3SO2O– Dr. Wolf's CHM 201 & 202 105 108 TsOH CF3SO2OH 600 106 8-108 Tosylates can be converted to Tosylates can be converted to alkyl halides alkyl halides CH3CHCH2CH3 OTs NaBr DMSO SN2 CH3CHCH2CH3 Br (82%) • Tosylate is a better leaving group than bromide. Dr. Wolf's CHM 201 & 202 8-109 Tosylates allow control of Tosylates allow control of stereochemistry stereochemistry • Preparation of tosylate does not affect any of the bonds to the stereogenic center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed. H CH3(CH2)5 TsCl C CH3(CH2)5 H C OH OTs pyridine H3C Dr. Wolf's CHM 201 & 202 H3C 8-110 Tosylates allow control of Tosylates allow control of stereochemistry stereochemistry • Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes. CH3(CH2)5 H H C OTs Nu– S N2 H3C Dr. Wolf's CHM 201 & 202 (CH2)5CH3 Nu C CH3 8-111 Looking Back: Reactions of Alcohols with Hydrogen Halides Dr. Wolf's CHM 201 & 202 8-112 Secondary alcohols Secondary alcohols react with hydrogen halides with net inversion of configuration H CH3 Br C 87% H H3C C CH3(CH2)5 OH HBr 13% Since some racemization, can’t be SN2 Dr. Wolf's CHM 201 & 202 (CH2)5CH3 H H3C C Br CH3(CH2)5 8-113 Secondary alcohols Secondary alcohols react with hydrogen halides with net inversion of configuration H • H CH3 Br C 87% (CH2)5CH3 H3C Most reasonable mechanism is SN1 with front side of HBr C OH carbocation shielded by leaving group CH3(CH2)5 13% H H3C C Br CH3(CH2)5 Dr. Wolf's CHM 201 & 202 8-114 Rearrangements Rearrangements can occur in the reaction of alcohols with hydrogen halides OH OH HBr Br Br + Br Br 93% Dr. Wolf's CHM 201 & 202 7% 8-115 Rearrangements Rearrangements HBr OH OH 7% + 93% Br – Br + Br Br Br – Br + Br Br Dr. Wolf's CHM 201 & 202 8-116 End of Chapter 8 Dr. Wolf's CHM 201 & 202 8-117 ...
View Full Document

Ask a homework question - tutors are online