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