chapter 8 NUCLEOPHILIC SUBSTITUTION SOLUTIONS TO TEXT PROBLEMS 8.1 Identify the nucleophilic anion in each reactant. The nucleophilic anion replaces bromine as a sub- (b) Potassium ethoxide serves as a source of the nucleophilic anion CH CH,O CH, CH,O: CH Bra CH3CH2OCH3 Br: Ethoxide ion Methyl bromide Ethyl methyl ether Bromide ion B3 Br: Br Benzoate ion Methyl bromide Methyl benzoate (d) Lithium azide is a source of the azide ion. It reacts with methyl bromide to give methyl azide NN=N:+ CH B1 CHNE N=N:+1 Azide ior Methyl azide Bromide ion (nucleophile) (e) The nucleophilic anion in KCN is cyanide(CEN: ) The carbon atom is negatively charged and is normally the site of nucleophilic reactivity Cyanide Methyl bromide Methyl cyanide romine ion 184 Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
CHAPTER 8 NUCLEOPHILIC SUBSTITUTION SOLUTIONS TO TEXT PROBLEMS 8.1 Identify the nucleophilic anion in each reactant. The nucleophilic anion replaces bromine as a substituent on carbon. (b) Potassium ethoxide serves as a source of the nucleophilic anion CH3CH2O. (c) (d) Lithium azide is a source of the azide ion. It reacts with methyl bromide to give methyl azide. (e) The nucleophilic anion in KCN is cyanide ( ). The carbon atom is negatively charged and is normally the site of nucleophilic reactivity. CH3Br CH3C N Br Methyl cyanide Bromide ion (product) Methyl bromide N C Cyanide ion (nucleophile) C N N N N N N CH3Br CH3N Br Methyl azide Bromide ion (product) Methyl bromide Azide ion (nucleophile) N N N CH3Br Br Benzoate ion Methyl bromide Methyl benzoate Bromide ion C O O C OCH3 O CH3CH2O CH3Br CH3CH2OCH3 Br Ethyl methyl ether Bromide ion (product) Ethoxide ion Methyl bromide (nucleophile) 184 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
NUCLEOPHILIC SUBSTITUTION 185 (f) The anion in sodium hydrogen sulfide(NasH)is : SH CH3SH Br Hydrogen Methyl bro Methanethiol Bromide ion (g) Sodium iodide is a source of the nucleophilic anion iodide ion, I The reaction of sodium iodide with alkyl bromides is usually carried out in acetone to precipitate the sodium bromide Br: lodide ion Methyl bromide Methyl iodide Bromide ion 8.2 Write out the structure of the starting material. Notice that it contains a primary bromide and a pri mary chloride. Bromide is a better leaving group than chloride and is the one that is displaced faster by the nucleophilic cyanide ion. CICH..Br NaCN ethanokwater CICHCH2CHC≡N 1-Bromo-3-chloropropane 8.3 No, the two-step sequence is not consistent with the observed behavior for the hydrolysis of methyl bromide. The rate-determining step in the two-step sequence shown is the first step, ionization of methyl bromide to give methyl cation CH Br CH,+ Br 2. CH2 HO In such a sequence the nucleophile would not participate in the reaction until after the rate- determining step is past, and the reaction rate would depend only on the concentration of methyl bromide and be independent of the concentration of hydroxide ion. The predicted kinetic behavior is first order. Second order kinetic behavior is actually observed for methyl bromide hydrolysis, so the proposed mechanism cannot be correct. 8.4 Inversion of configuration occurs at the stereogenic center. When shown in a Fischer projection, his corresponds to replacing the leaving group on the one side by the nucleophile on the opposite NaOH HO-+H CH(CH2)4CH3 CH2(CH2)4CH3 (S-(+)-2-Bromooctan (R)(-)-2-Octanol 8.5 The example given in the text illustrates inversion of configuration in the S2 hydrolysis of (S)-(+)-2-bromooctane, which yields(R)-(-)-2-octanol. The hydrolysis of(R)-(-)-2-bromooctane exactly mirrors that of its enantiomer and yields(S)-(+)-2-octanol ants must yield optically inactive products 8.6 Sodium iodide in acetone is a reagent that converts alkyl chlorides and bromides into alkyl io- dides by an Sn2 mechanism. Pick the alkyl halide in each pair that is more reactive toward Sn2 Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
( f ) The anion in sodium hydrogen sulfide (NaSH) is . (g) Sodium iodide is a source of the nucleophilic anion iodide ion, . The reaction of sodium iodide with alkyl bromides is usually carried out in acetone to precipitate the sodium bromide formed. 8.2 Write out the structure of the starting material. Notice that it contains a primary bromide and a primary chloride. Bromide is a better leaving group than chloride and is the one that is displaced faster by the nucleophilic cyanide ion. 8.3 No, the two-step sequence is not consistent with the observed behavior for the hydrolysis of methyl bromide. The rate-determining step in the two-step sequence shown is the first step, ionization of methyl bromide to give methyl cation. 1. 2. In such a sequence the nucleophile would not participate in the reaction until after the ratedetermining step is past, and the reaction rate would depend only on the concentration of methyl bromide and be independent of the concentration of hydroxide ion. Rate k[CH3Br] The predicted kinetic behavior is first order. Second order kinetic behavior is actually observed for methyl bromide hydrolysis, so the proposed mechanism cannot be correct. 8.4 Inversion of configuration occurs at the stereogenic center. When shown in a Fischer projection, this corresponds to replacing the leaving group on the one side by the nucleophile on the opposite side. 8.5 The example given in the text illustrates inversion of configuration in the SN2 hydrolysis of (S)-()-2-bromooctane, which yields (R)-()-2-octanol. The hydrolysis of (R)-()-2-bromooctane exactly mirrors that of its enantiomer and yields (S)-()-2-octanol. Hydrolysis of racemic 2-bromooctane gives racemic 2-octanol. Remember, optically inactive reactants must yield optically inactive products. 8.6 Sodium iodide in acetone is a reagent that converts alkyl chlorides and bromides into alkyl iodides by an SN2 mechanism. Pick the alkyl halide in each pair that is more reactive toward SN2 displacement. NaOH SN2 CH3 CH2(CH2)4CH3 H Br CH3 CH2(CH2)4CH3 HO H (S)-()-2-Bromooctane (R)-()-2-Octanol CH3 HO CH3OH fast CH3Br CH3 Br slow ClCH2CH2CH2Br 1-Bromo-3-chloropropane 4-Chlorobutanenitrite NaCN ethanol–water ClCH2CH2CH2C N CH3Br Br CH3 Iodide ion Methyl bromide Methyl iodide Bromide ion I I acetone I HS CH3Br CH3SH Br Hydrogen Methyl bromide Methanethiol Bromide ion sulfide ion SH NUCLEOPHILIC SUBSTITUTION 185 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
186 NUCLEOPHILIC SUBSTITUTION (b) The less crowded alkyl halide reacts faster in an SN2 reaction. 1-Bromopentane is a primary alkyl halide and so is more reactive than 3-bromopentane, which is secondary BrCH,CH,CH,CH,CH CH, CH, CHCH, CH 1-Bromopentane 3-Bromopentane more reactive in SN2)(secondary; less reactive in SN2) (c) Both halides are secondary, but fluoride is a poor leaving group in nucleophilic substitution reactions. Alkyl chlorides are more reactive than alkyl fluorides CHa CHCH, CH, CH, CH3 CHCH,CH, CH3 2-Chloropentane 2-Fluoropentane ( more reactive) (less reactive) (d) A secondary alkyl bromide reacts faster under Sn2 conditions than a tertiary one CH, CHCH, CH,CHCH; CH,, CH,, CH3 2-Bromo-5-methy lhexane 2-Bromo-2-methylhexan (secondary; more reactive in Sn2) (tertiary; less reactive in SN2) (e) The number of carbons does not matter as much as the degree of substitution at the reaction site. The primary alkyl bromide is more reactive than the secondar BrCH,(CH,)CH CH CHCH 1-Bromodecane rimary:more reactive in Sx2) (secondary; less reactive in SN2) 8.7 Nitrite ion has two potentially nucleophilic sites, oxygen and nitroger 2: R+: Nitrite ion Alkyl iodide Iodide ion N-R 88 Nitrite io Alkyl iodide Nitroalkane lodide ion Thus, an alkyl iodide can yield either an alkyl nitrite or a nitroalkane depending on whether the oxy gen or the nitrogen of nitrite ion attacks carbon. Both do, and the product from 2-iodooctane is a mixture of CH,CH(CH2)5CH3 and CH,CH(CH,)5CH3 Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
186 NUCLEOPHILIC SUBSTITUTION (b) The less crowded alkyl halide reacts faster in an SN2 reaction. 1-Bromopentane is a primary alkyl halide and so is more reactive than 3-bromopentane, which is secondary. (c) Both halides are secondary, but fluoride is a poor leaving group in nucleophilic substitution reactions. Alkyl chlorides are more reactive than alkyl fluorides. (d) A secondary alkyl bromide reacts faster under SN2 conditions than a tertiary one. (e) The number of carbons does not matter as much as the degree of substitution at the reaction site. The primary alkyl bromide is more reactive than the secondary. 8.7 Nitrite ion has two potentially nucleophilic sites, oxygen and nitrogen. Thus, an alkyl iodide can yield either an alkyl nitrite or a nitroalkane depending on whether the oxygen or the nitrogen of nitrite ion attacks carbon. Both do, and the product from 2-iodooctane is a mixture of CH3CH(CH2)5CH3 CH3CH(CH2)5CH3 ONO NO2 and N R N R Nitrite ion Alkyl iodide Nitroalkane Iodide ion I I O O O O ON R O I ON R O Nitrite ion Alkyl iodide Alkyl nitrite Iodide ion I BrCH2(CH2)8CH3 CH3CHCH3 Br 2-Bromopropane (secondary; less reactive in SN2) 1-Bromodecane (primary; more reactive in SN2) CH3CHCH2CH2CHCH3 Br CH3 CH3CCH2CH2CH2CH3 Br CH3 2-Bromo-2-methylhexane (tertiary; less reactive in SN2) 2-Bromo-5-methylhexane (secondary; more reactive in SN2) CH3CHCH2CH2CH3 F 2-Fluoropentane (less reactive) CH3CHCH2CH2CH3 Cl 2-Chloropentane (more reactive) BrCH2CH2CH2CH2CH3 CH3CH2CHCH2CH3 Br 3-Bromopentane (secondary; less reactive in SN2) 1-Bromopentane (primary; more reactive in SN2) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
NUCLEOPHILIC SUBSTITUTION 187 8.8 Solvolysis of alkyl halides in alcohols yields ethers as the products of reaction (CH3)CBr CH,OH -(CH3)3COCH3 HBr Methanol tert-Butyl methy Hydrogen he reaction proceeds by an Snl mechanism. (CH3) C-Br (CH3)3 Br tert-Butyl tert-Butyl Bromide bromid CH CH3 (CH3)2 tert-Butyl Methanol tert-Butyloxonium (CH3)2C-O3 Br: -(CH3)3C-OCH3 H-Br terT-Butyloxonium BromI Hydrogen methyl 8.9 The reactivity of an alkyl halide in an SNl reaction is dictated by the ease with which it ionizes form a carbocation. Tertiary alkyl halides are the most reactive, methyl halides the least reactive (b) Cyclopentyl iodide ionizes to form a secondary carbocation, and the carbocation from 1-methylcyclopentyl iodide is tertiary. The tertiary halide is more reactive (tertiary: more reactive in SI)(secondary; less reactive in SNI) (c) Cyclopentyl bromide ionizes to a secondary carbocation. l-Bromo-2, 2-dimethyl-propane is a primary alkyl halide and is therefore less reactive. ( CH3)3CCH,Br Cyclopentyl bromide I-Bromo-2, 2-dimethylpropane (secondary; more reactive in SNI)(primary: less reactive in SNl) (d) lodide is a better leaving group than chloride in both SNI and Sn2 reactions (CH3)3CI (CH3)CCI m tert-Butyl chloride (less reactive) Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
8.8 Solvolysis of alkyl halides in alcohols yields ethers as the products of reaction. The reaction proceeds by an SN1 mechanism. 8.9 The reactivity of an alkyl halide in an SN1 reaction is dictated by the ease with which it ionizes to form a carbocation. Tertiary alkyl halides are the most reactive, methyl halides the least reactive. (b) Cyclopentyl iodide ionizes to form a secondary carbocation, and the carbocation from 1-methylcyclopentyl iodide is tertiary. The tertiary halide is more reactive. (c) Cyclopentyl bromide ionizes to a secondary carbocation. 1-Bromo-2,2-dimethyl-propane is a primary alkyl halide and is therefore less reactive. (d) Iodide is a better leaving group than chloride in both SN1 and SN2 reactions. (CH3)3CI (CH3)3CCl tert-Butyl chloride (less reactive) tert-Butyl iodide (more reactive) H Br Cyclopentyl bromide (secondary; more reactive in SN1) 1-Bromo-2,2-dimethylpropane (primary; less reactive in SN1) (CH3)3CCH2Br H I 3C 1-Methylcyclopentyl iodide (tertiary; more reactive in SN1) H I Cyclopentyl iodide (secondary; less reactive in SN1) tert-Butyloxonium ion (CH3)3C O H CH3 tert-Butyl methyl ether (CH3)3C OCH3 Bromide ion Br Hydrogen bromide H Br tert-Butyloxonium ion tert-Butyl cation Methanol fast (CH3)3C O (CH3)3C O CH3 H CH3 H (CH3)3C Br Bromide ion tert-Butyl bromide tert-Butyl cation (CH3)3C Br slow (CH3)3CBr (CH CH3OH HBr 3)3COCH3 Hydrogen bromide tert-Butyl methyl ether tert-Butyl Methanol bromide NUCLEOPHILIC SUBSTITUTION 187 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
188 NUCLEOPHILIC SUBSTITUTION 8.10 The alkyl halide is tertiary and so undergoes hydrolysis by an SxI mechanism. The carbocation car be captured by water at either face. A mixture of the axial and the equatorial alcohols is formed is-1, 4-Dimethylcyclohexyl bromide H, C trans-1, 4-Dimethylcyclohexanol Carbocation intermediate cis-1, 4-Dimethylcyclohexanol The same two substitution products are formed from trans-1, 4-dimethylcyclohexyl bromide be- cause it undergoes hydrolysis via the same carbocation intermediate 8.11 Write chemical equations illustrating each rearrangement process Hydride shift: H,C-C--CCH H C-C- Tertiary carbocation Methyl shift: H3CCC--CH3 H CH. CH Secondary carbocation Rearrangement by a hydride shift is observed because it converts a secondary carbocation to a more stable tertiary one. A methyl shift gives a secondary carbocation--in this case the same carbocation as the one that existed prior to rearrangement 8.12(b) Ethyl bromide is a primary alkyl halide and reacts with the potassium salt of cyclohexanol by substitution CH CHBr OCH,CH3 Ethyl bromide Potassium Cyclohexyl ethyl ether (c) No strong base is present in this reaction; the nucleophile is methanol itself, not methoxide. It reacts with sec-butyl bromide by substitution, not elimination CH_CHCH,CH3 CH,OH CH CHCH, CH3 OCH sec-Butyl bromide sec-Butyl methyl ether Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
8.10 The alkyl halide is tertiary and so undergoes hydrolysis by an SN1 mechanism. The carbocation can be captured by water at either face. A mixture of the axial and the equatorial alcohols is formed. The same two substitution products are formed from trans-1,4-dimethylcyclohexyl bromide because it undergoes hydrolysis via the same carbocation intermediate. 8.11 Write chemical equations illustrating each rearrangement process. Hydride shift: Methyl shift: Rearrangement by a hydride shift is observed because it converts a secondary carbocation to a more stable tertiary one. A methyl shift gives a secondary carbocation—in this case the same carbocation as the one that existed prior to rearrangement. 8.12 (b) Ethyl bromide is a primary alkyl halide and reacts with the potassium salt of cyclohexanol by substitution. (c) No strong base is present in this reaction; the nucleophile is methanol itself, not methoxide. It reacts with sec-butyl bromide by substitution, not elimination. CH3OH sec-Butyl bromide CH3CHCH2CH3 Br CH3CHCH2CH3 OCH3 sec-Butyl methyl ether OK Potassium cyclohexanolate OCH2CH3 Cyclohexyl ethyl ether CH3CH2Br Ethyl bromide Secondary carbocation C C H H CH3 H3C CH3 C C H CH3 H3C H CH3 Tertiary carbocation C CCH3 H CH3 H H3C C C H H H3C CH3 CH3 cis-1,4-Dimethylcyclohexyl bromide CH3 Br H3C trans-1,4-Dimethylcyclohexanol OH CH3 H3C cis-1,4-Dimethylcyclohexanol CH3 OH H3C Carbocation intermediate CH3 H3C H2O H2O 188 NUCLEOPHILIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
NUCLEOPHILIC SUBSTITUTION 189 (d) Secondary alkyl halides react with alkoxide bases by E2 elimination NaoH CH CHCHCH CH,OH CH, CH=CHCH3 H2C=CHCH2CH sec-Butyl bromide 2-Buter -Butene (major product; mixture of cis and trans 8.13 Alkyl p-toluenesulfonates are prepared from alcohols and p-toluenesulfonyl chloride. CHa(CH,)1CH,OH HaC CHa(CH,)ICH,OS -Ch HCI -Octadecanol Octadecyl p-toluenesulfonate chloride 8.14 As in part(a), identify the nucleophilic anion in each part. The nucleophile replaces the p-toluene- sulfonate(tosylate)leaving group by an SN2 process. The tosylate group is abbreviated as OTs CH(CH,)1 Ch,Ots CH3(CH,) CH,I t Tso none pioloehestonate (c) CEN CH, (CH,),CHOTs CH(CH2)16CH2C≡N+TsO Octadecyl (d) HS CH3(CH,)16CHOTS CH3(CH)16 CH2SH Tso Octadecyl Octadecanethiol P-Tol CH,, CH,CH,S CH3(CH,)1CH,OTS CHa(CH,)CH,SCH,CH,CH,CH3 t TsO Octadecyl Butyl octadecyl p-Toluenesulfonate 8.15 The hydrolysis of (S)-(+)-1-methy heptyl p-toluenesulfonate proceeds with inversion of configura- tion, giving the R enantiomer of 2-0 CH3(CH,) (CH,)5CH (S)-(+)-1-Methylheptyl In Section 8. 14 of the text we are told that optically pure(S)-(+)-l-methy heptyl p-toluenesulfonate is prepared from optically pure (S)-(+)-2-octanol having a specific rotation [a]b +9.9%. The of an alcohol to a p-toluenesulfonate proceeds with complete retention of configuration Hydrolysis of this p-toluenesulfonate with inversion of configuration therefore yields optically pure (R)-(-)-2-octanol of [a]D-9.9% Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(d) Secondary alkyl halides react with alkoxide bases by E2 elimination. 8.13 Alkyl p-toluenesulfonates are prepared from alcohols and p-toluenesulfonyl chloride. 8.14 As in part (a), identify the nucleophilic anion in each part. The nucleophile replaces the p-toluenesulfonate (tosylate) leaving group by an SN2 process. The tosylate group is abbreviated as OTs. (b) (c) (d) (e) 8.15 The hydrolysis of (S)-()-1-methylheptyl p-toluenesulfonate proceeds with inversion of configuration, giving the R enantiomer of 2-octanol. In Section 8.14 of the text we are told that optically pure (S)-()-1-methylheptyl p-toluenesulfonate is prepared from optically pure (S)-()-2-octanol having a specific rotation [] 25 D 9.9°. The conversion of an alcohol to a p-toluenesulfonate proceeds with complete retention of configuration. Hydrolysis of this p-toluenesulfonate with inversion of configuration therefore yields optically pure (R)-()-2-octanol of [] 25 D 9.9°. CH H 3(CH2)5 H3C C OTs H HO (CH2)5CH3 CH3 C H2O (S)-()-1-Methylheptyl p-toluenesulfonate (R)-()-2-Octanol CH3(CH2) CH 16CH2OTs 3CH2CH2CH2 S Butanethiolate ion CH3(CH2)16CH2SCH2CH2CH2CH3 TsO Octadecyl p-toluenesulfonate Butyl octadecyl thioether p-Toluenesulfonate anion HS Hydrogen sulfide ion CH3(CH2)16CH2OTs CH3(CH2)16 CH2SH Octadecyl p-toluenesulfonate 1-Octadecanethiol TsO p-Toluenesulfonate anion C Cyanide ion N CH3(CH2)16 CH2OTs Octadecyl p-toluenesulfonate CH3(CH2)16CH2 Octadecyl cyanide TsO p-Toluenesulfonate anion C N CH3(CH2)16CH2OTs CH3(CH2)16CH2I TsO Octadecyl p-toluenesulfonate Octadecyl iodide p-Toluenesulfonate anion I Iodide ion CH3(CH2)16CH2OH 1-Octadecanol p-Toluenesulfonyl chloride Octadecyl p-toluenesulfonate Hydrogen chloride SCl O O H3C CH HCl 3 O O CH3(CH2)16CH2OS pyridine sec-Butyl bromide CH3CHCH2CH3 Br CH3CH 2-Butene (major product; mixture of cis and trans) NaOCH3 CH3OH CHCH3 CHCH2CH3 1-Butene H2C NUCLEOPHILIC SUBSTITUTION 189 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
190 NUCLEOPHILIC SUBSTITUTION 8.16 Protonation of 3-methyl-2-butanol and dissociation of the alkyloxonium ion gives a secondary carbocation. A hydride shift yields a tertiary, and thus more stable, carbocation. Capture of this car- bocation by chloride ion gives the major product, 2-chloro-2-methylbutane CH, CHCH(CH3) CH, CHCH(CH3), bym→CHCH2C(CH3)2 3-Methyl-2-butanol Secondary carbocation; Tertiary carbocation; less sta more stable CH3 CHCH(CH3)2 CH3CH, C(CH3) 2-Chloro-3-methylbutane trace 8.17 1-Bromopropane is a primary alkyl halide, and so it will undergo predominantly SN2 displacement regardless of the basicity of the nucleophile (a) CH, CH, CH Br Nal_ CH3 CH, CH,I CH: CONa b)CHCH2CH2Br“ acetic acid→CH2CH2CH2OCCH (c) CH3CH2 CH, BI CH3,,OCH, CH3 Ethyl propyl ether CH CHCI NaCN CH3 CH,CH,CN Butanenitrile (e) CHCH,CH, Br CH3CHCH,N (f) CH, CH,CH, Br NaSH CHa,CH,SH NaSCH (8) CH3 CH2 CH_- ethanol CH,CH,CH2SCH Methyl propyl sulfide 8.18 Elimination is the major product when secondary halides react with anions as basic as or more basic than hydroxide ion Alkoxide ions have a basicity comparable with hydroxide ion and react with Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
8.16 Protonation of 3-methyl-2-butanol and dissociation of the alkyloxonium ion gives a secondary carbocation. A hydride shift yields a tertiary, and thus more stable, carbocation. Capture of this carbocation by chloride ion gives the major product, 2-chloro-2-methylbutane. 8.17 1-Bromopropane is a primary alkyl halide, and so it will undergo predominantly SN2 displacement regardless of the basicity of the nucleophile. (a) (b) (c) (d) (e) ( f ) (g) 8.18 Elimination is the major product when secondary halides react with anions as basic as or more basic than hydroxide ion. Alkoxide ions have a basicity comparable with hydroxide ion and react with CH3CH2CH2Br NaSCH3 ethanol Methyl propyl sulfide CH3CH2CH2SCH3 CH3CH2CH2Br NaSH ethanol 1-Propanethiol CH3CH2CH2SH CH3CH2CH2Br NaN3 ethanol–water 1-Azidopropane CH3CH2CH2N3 CH3CH2CH2Br NaCN DMSO Butanenitrite CH3CH2CH2CN CH3CH2CH2Br NaOCH2CH3 ethanol Ethyl propyl ether CH3CH2CH2OCH2CH3 CH3CH2CH2Br CH3CONa acetic acid Propyl acetate CH3CH2CH2OCCH3 O O CH3CH2CH2Br CH3CH2CH2I NaI acetone 1-Bromopropane 1-Iodopropane CH3CHCH(CH3)2 OH 3-Methyl-2-butanol HCl CH3CHCH(CH3)2 Secondary carbocation; less stable CH3CH2C(CH3)2 Tertiary carbocation; more stable Cl Cl Cl CH3CHCH(CH3)2 Cl 2-Chloro-3-methylbutane (trace) CH3CH2 C(CH3)2 2-Chloro-2-methylbutane (major product; 97%) hydride shift 190 NUCLEOPHILIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
NUCLEOPHILIC SUBSTITUTION 191 secondary halides to give predominantly elimination products. Thus ethoxide ion [part(c)] will react with 2-bromopropane to give mainly propene NaOCHAC CH3CHCH3 CHICH=CH, Pro 8.19 (a) The substrate is a primary alkyl bromide and reacts with sodium iodide in acetone to give the corresponding iodide. BrChcoChcH ICH,COCH, CH3 Ethyl iodoacetate(89%) (b) Primary alkyl chlorides react with sodium acetate to yield the corresponding acetate esters CHACON CHO O,N CHOCCH (c) The only leaving group in the substrate is bromide. Neither of the carbon-oxygen bonds is susceptible to cleavage by nucleophilic attack CH3 CH,OCH, CH,Br aNa→ CHa CH,OCH,CH,CN 2-Bromoethyl ethyl ether 2-Cyanoethyl ethyl ether (52-58% (d) Hydrolysis of the primary chloride yields the corresponding alcohol H.O. HO CHCI NC CHOH p-Cyanobenzyl chloride zyl alcohol (85%o) (e) The substrate is a primary chloride CICH,COC(CH3)3 acetone-water NaCH, COC(CH3) tert-Butyl chloroacetate tert-Butyl azidoacetate(92%) (f) Primary alkyl tosylates yield iodides on treatment with sodium iodide in acetone CH TSOCHO CH ICHO (2, 2-Dimethy l-1, 3-dioxolan-4-yl)- ethyl p-toluenesulfonate (60%) g) Sulfur displaces bromide from ethyl bromide. CH, SNa CH Br O CH,SCH, CH Sodium (2-fur Ethyl bromide Ethyl (2-furyl)methyl llfide(80%) Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
secondary halides to give predominantly elimination products. Thus ethoxide ion [part (c)] will react with 2-bromopropane to give mainly propene. 8.19 (a) The substrate is a primary alkyl bromide and reacts with sodium iodide in acetone to give the corresponding iodide. (b) Primary alkyl chlorides react with sodium acetate to yield the corresponding acetate esters. (c) The only leaving group in the substrate is bromide. Neither of the carbon–oxygen bonds is susceptible to cleavage by nucleophilic attack. (d) Hydrolysis of the primary chloride yields the corresponding alcohol. (e) The substrate is a primary chloride. ( f ) Primary alkyl tosylates yield iodides on treatment with sodium iodide in acetone. (g) Sulfur displaces bromide from ethyl bromide. O CH CH3CH2Br 2SNa O CH2SCH2CH3 Sodium (2-furyl)- methanethiolate Ethyl bromide Ethyl (2-furyl)methyl sulfide (80%) TsOCH2 CH3 CH3 O O ICH2 CH3 CH3 O O NaI acetone (2,2-Dimethyl-1,3-dioxolan-4-yl)- methyl p-toluenesulfonate 2,2-Dimethyl-4-(iodomethyl)- 1,3-dioxolane (60%) NaN3 acetone–water tert-Butyl chloroacetate tert-Butyl azidoacetate (92%) ClCH2COC(CH3)3 O N3CH2COC(CH3)3 O NC CH2Cl NC CH2OH H2O, HO p-Cyanobenzyl chloride p-Cyanobenzyl alcohol (85%) NaCN ethanol–water 2-Cyanoethyl ethyl ether (52–58%) 2-Bromoethyl ethyl ether CH3CH2OCH2CH2Br CH3CH2OCH2CH2CN O2N CH2Cl p-Nitrobenzyl chloride O2N CH2OCCH3 O p-Nitrobenzyl acetate (78–82%) CH3CONa O acetic acid NaI acetone Ethyl bromoacetate Ethyl iodoacetate (89%) ICH2COCH2CH3 O BrCH2COCH2CH3 O CH3CHCH3 NaOCH2CH3 Propene Br CH3CH CH2 NUCLEOPHILIC SUBSTITUTION 191 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
192 NUCLEOPHILIC SUBSTITUTION (h) The first reaction is one in which a substituted alcohol is converted to a p-toluenesulfonate ester. This is followed by an SN2 displacement with lithium iodide OCH3 OCH CH,CH, CH,CHOH CH,CH,CH,CH,OTS pyridine(6 CH, O CH O 4-(2, 3, 4-Trimethoxyphenyl)-1-butanol OCH CHO CH,CH,CH,CH,I CHO 4-(2, 3. 4-Trimethoxyphenyl)-l-butyl iodide 8.20 The two products are diastereomers of each other. They are formed by bimolecular nucleophilic sub stitution(SN2). In each case, a good nucleophile(C HsS) displaces chloride from a secondary (a) The trans chloride yields a cis substitution product. C(CH3) C(CH3)3+ sN一 trans-4-terI-Butylcyclohexyl Sodium cis-4-tert-Butylcyclohexyl phenyl sulfide benzenethiolate (b) The cis chloride yields a trans substitution product. s-4-tert-Butylcyclohexyl Sodiur trans-4-terl-Butylcyclohexyl phenyl 8.21 The isomers of CHoCl are CHa CH,CH,CH,CI CHCHCHCI 1-Chloro-2-methylpropane (n-butyl chloride) (isobutyl chloride) CHa CHCH,CH3 CH CCI The reaction conditions(sodium iodide in acetone) are typical for an Sn2 process Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(h) The first reaction is one in which a substituted alcohol is converted to a p-toluenesulfonate ester. This is followed by an SN2 displacement with lithium iodide. 8.20 The two products are diastereomers of each other. They are formed by bimolecular nucleophilic substitution (SN2). In each case, a good nucleophile (C6H5S) displaces chloride from a secondary carbon with inversion of configuration. (a) The trans chloride yields a cis substitution product. (b) The cis chloride yields a trans substitution product. 8.21 The isomers of C4H9Cl are: The reaction conditions (sodium iodide in acetone) are typical for an SN2 process. 2-Chlorobutane (sec-butyl chloride) 2-Chloro-2-methylpropane (tert-butyl chloride) CH3CCl CH3 CH3 CH3CHCH2CH3 Cl 1-Chlorobutane (n-butyl chloride) 1-Chloro-2-methylpropane (isobutyl chloride) CH3CH2CH2CH2Cl CH3CHCH2Cl CH3 cis-4-tert-Butylcyclohexyl chloride C(CH3)3 Cl trans-4-tert-Butylcyclohexyl phenyl sulfide S C(CH3) 3 Sodium benzenethiolate NaS SNa Sodium benzenethiolate trans-4-tert-Butylcyclohexyl chloride C(CH3)3 Cl cis-4-tert-Butylcyclohexyl phenyl sulfide S C(CH3)3 CH CH2CH2CH2CH2OTs 3O CH3O CH2CH2CH2CH2 CH I 3O CH3O OCH3 OCH3 TsCl pyridine (62%) LiI, acetone (88%) OCH3 CH3O CH2CH2CH2CH2OH CH3O 4-(2,3,4-Trimethoxyphenyl)-1-butanol 4-(2,3,4-Trimethoxyphenyl)-1-butyl iodide 192 NUCLEOPHILIC SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
NUCLEOPHILIC SUBSTITUTION 193 The order of Sx2 reactivity is primary >secondary tertiary, and branching of the chain close to the site of substitution hinders reaction. The unbranched primary halide n-butyl chloride will be the most reactive and the tertiary halide tert-butyl chloride the least. The order of reactivity will therefore be: 1-chlorobutane 1-chloro-2-methylpropane 2-chlorobutane > 2-chloro-2 8.22 1-Chlorohexane is a primary alkyl halide; 2-chlorohexane and 3-chlorohexane are secondary CHaCH,CHL CH,CH,CH,CI CH CHCH, CH,, CH3 CH3 CH, CHCH, CH,CH= 1-Chlorohexane 2-Chlorohexane 3. chlorohexane Primary and secondary alkyl halides react with potassium iodide in acetone by an Sn2 mechanism, and the rate depends on steric hindrance to attack on the alkyl halide by the nucleophile (a) Primary alkyl halides are more reactive than secondary alkyl halides in Sn2 reactions 1-Chlorohexane is the most reactive isomer (b) Substituents at the carbon adjacent to the one that bears the leaving group slow down the rate of nucleophilic displacement. In 2-chlorohexane the group adjacent to the point of attack is CH3. In 3-chlorohexane the group adjacent to the point of attack is CH, CH3. 2-Chlorohexane has been observed to be more reactive than 3-chlorohexane by a factor of 2. 8.23 (a) lodide is a better leaving group than bromide, and so 1-iodobutane should undergo Sn2 attack by cyanide faster than 1-bromobutane (b) The reaction conditions are typical for an Sn2 process. The methyl branch in 1-chloro- 2-methylbutane sterically hinders attack at C-1. The unbranched isomer, 1-chloropentane,re- CHaCH, CHCH,CI CH,CHaCH,CH,CH,CI hore sterically hindered. therefore more (c) Hexyl chloride is a primary alkyl halide, and cyclohexyl chloride is secondary. Azide ion is a ood nucleophile so the s2 reactivity rules apply; primary is more reactive than CH CH, CH, CH,CH,CH,CI Hexyl chloride is prima therefore more reactive i (d) 1-Bromo-2, 2-dimethylpropane is too hindered to react with the weakly nucleophilic ethanol by an SN2 reaction, and since it is a primary alkyl halide, it is less reactive in Snl reactions tert-Butyl bromide will react with ethanol by an SxI mechanism at a reasonable rate owing to formation of a tertiary carbocation (CH3),CBr (CH3)3 CCH, Br tert-Butyl bromide; more reactive In latively unreactive in nucleophilic SNI solvolysis Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
The order of SN2 reactivity is primary secondary tertiary, and branching of the chain close to the site of substitution hinders reaction. The unbranched primary halide n-butyl chloride will be the most reactive and the tertiary halide tert-butyl chloride the least. The order of reactivity will therefore be: 1-chlorobutane 1-chloro-2-methylpropane 2-chlorobutane 2-chloro-2- methylpropane. 8.22 1-Chlorohexane is a primary alkyl halide; 2-chlorohexane and 3-chlorohexane are secondary. Primary and secondary alkyl halides react with potassium iodide in acetone by an SN2 mechanism, and the rate depends on steric hindrance to attack on the alkyl halide by the nucleophile. (a) Primary alkyl halides are more reactive than secondary alkyl halides in SN2 reactions. 1-Chlorohexane is the most reactive isomer. (b) Substituents at the carbon adjacent to the one that bears the leaving group slow down the rate of nucleophilic displacement. In 2-chlorohexane the group adjacent to the point of attack is CH3. In 3-chlorohexane the group adjacent to the point of attack is CH2CH3. 2-Chlorohexane has been observed to be more reactive than 3-chlorohexane by a factor of 2. 8.23 (a) Iodide is a better leaving group than bromide, and so 1-iodobutane should undergo SN2 attack by cyanide faster than 1-bromobutane. (b) The reaction conditions are typical for an SN2 process. The methyl branch in 1-chloro- 2-methylbutane sterically hinders attack at C-1. The unbranched isomer, 1-chloropentane, reacts faster. (c) Hexyl chloride is a primary alkyl halide, and cyclohexyl chloride is secondary. Azide ion is a good nucleophile, and so the SN2 reactivity rules apply; primary is more reactive than secondary. (d) 1-Bromo-2,2-dimethylpropane is too hindered to react with the weakly nucleophilic ethanol by an SN2 reaction, and since it is a primary alkyl halide, it is less reactive in SN1 reactions. tert-Butyl bromide will react with ethanol by an SN1 mechanism at a reasonable rate owing to formation of a tertiary carbocation. (CH3)3CBr tert-Butyl bromide; more reactive in SN1 solvolysis (CH3)3CCH2Br 1-Bromo-2,2-dimethylpropane; relatively unreactive in nucleophilic substitution reactions CH3CH2CH2CH2CH2CH2Cl Hexyl chloride is primary, therefore more reactive in SN2. Cyclohexyl chloride is secondary, therefore less reactive in SN2. Cl CH3CH2CHCH2Cl CH3 1-Chloro-2-methylbutane is more sterically hindered, therefore less reactive. CH3CH2CH2CH2CH2Cl 1-Chloropentane is less sterically hindered, therefore more reactive. 1-Chlorohexane (primary) CH3CH2CH2CH2CH2CH2Cl 2-Chlorohexane (secondary) Cl CH3CHCH2CH2CH2CH3 3-Chlorohexane (secondary) Cl CH3CH2CHCH2CH2CH3 NUCLEOPHILIC SUBSTITUTION 193 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website