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Unformatted text preview: CHAPTER 15 ALCOHOLS, DIOLS, AND THIOLS SOLUTIONS TO TEXT PROBLEMS 15.1 The two primary alcohols, 1-butanol and 2-methyl-1-propanol, can be prepared by hydrogenation of the corresponding aldehydes. O H2, Ni CH3CH2CH2CH CH3CH2CH2CH2OH Butanal 1-Butanol O H2, Ni (CH3)2CHCH 2-Methylpropanal (CH3)2CHCH2OH 2-Methyl-1-propanol The secondary alcohol 2-butanol arises by hydrogenation of a ketone. O H2, Ni CH3CCH2CH3 CH3CHCH2CH3 OH 2-Butanone 2-Butanol Tertiary alcohols such as 2-methyl-2-propanol, (CH3)3COH, cannot be prepared by hydrogenation of a carbonyl compound. 15.2 (b) A deuterium atom is transferred from NaBD4 to the carbonyl group of acetone. D BD3 CH3C O CH3 D CH3C D OBD3 3(CH3)2C CH3 O B CH3CO CH3 4 364 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 365 ALCOHOLS, DIOLS, AND THIOLS On reaction with CH3OD, deuterium is transferred from the alcohol to the oxygen of [(CH3)2CDO]4B. D D O CH3C B[OCD(CH3)2]3 CH3 D CH3COD D NaBD4 O (CH3)2C (CH3)2COD CH3OD Acetone 2-Propanol-2-d-O-d In this case NaBD4 serves as a deuterium donor to carbon, and CD3OH is a proton (not deuterium) donor to oxygen. D O NaBD4 C6H5CH C6H5CHOH CD3OH Benzaldehyde (d ) OCH3 CH3 OCH3 Overall: (c) B[OCD(CH3)2]3 Benzyl alcohol-1-d Lithium aluminum deuteride is a deuterium donor to the carbonyl carbon of formaldehyde. D D AlD3 HC O O OAlD3 HC H 3HCH (DCH2O)4Al H On hydrolysis with D2O, the oxygen–aluminum bond is cleaved and DCH2OD is formed. 4D2O Al(OCH2D)4 4DCH2OD Al(OD)4 Methanol-d-O-d 15.3 The acyl portion of the ester gives a primary alcohol on reduction. The alkyl group bonded to oxygen may be primary, secondary, or tertiary and gives the corresponding alcohol. O 1. LiAlH4 2. H2O Isopropyl propanoate 15.4 (b) CH3CH2CH2OH HOCH(CH3)2 1-Propanol CH3CH2COCH(CH3)2 2-Propanol Reaction with ethylene oxide results in the addition of a @ CH2CH2OH unit to the Grignard reagent. Cyclohexylmagnesium bromide (or chloride) is the appropriate reagent. MgBr H2C CH2 1. diethyl ether CH2CH2OH 2. H3O O Cyclohexylmagnesium bromide 15.5 Ethylene oxide 2-Cyclohexylethanol Lithium aluminum hydride is the appropriate reagent for reducing carboxylic acids or esters to alcohols. O O HOCCH2CHCH2COH 1. LiAlH4 2. H2O HOCH2CH2CHCH2CH2OH CH3 3-Methyl-1,5-pentanedioic acid Back Forward Main Menu CH3 3-Methyl-1,5-pentanediol TOC Study Guide TOC Student OLC MHHE Website 366 ALCOHOLS, DIOLS, AND THIOLS Any alkyl group may be attached to the oxygen of the ester function. In the following example, it is a methyl group. O O 1. LiAlH4 CH3OCCH2CHCH2COCH3 HOCH2CH2CHCH2CH2OH 2. H2O CH3 15.6 CH3 Dimethyl 3-methyl-1,5-pentanedioate 2CH3OH 3-Methyl-1,5-pentanediol Methanol Hydroxylation of alkenes using osmium tetraoxide is a syn addition of hydroxyl groups to the double bond. cis-2-Butene yields the meso diol. H H C (CH3)3COH, HO H H3C CH3 H3C OH HO OsO4, (CH3)3COOH C cis -2-Butene C C H CH3 meso-2,3-Butanediol trans-2-Butene yields a racemic mixture of the two enantiomeric forms of the chiral diol. CH3 H C H3C C (CH3)3COH, HO H H3C H trans-2-Butene H H3C H CC HO OH OH HO OsO4, (CH3)3COOH C C H3C CH3 H (2R,3R)-2,3-Butanediol (2S,3S )-2,3-Butanediol The Fischer projection formulas of the three stereoisomers are CH3 OH H H CH3 H HO H OH CH3 meso-2,3-Butanediol 15.7 OH CH3 (2R,3R)-2,3-Butanediol CH3 OH H HO H CH3 (2S,3S)-2,3-Butanediol The first step is proton transfer to 1,5-pentanediol to form the corresponding alkyloxonium ion. H HOCH2CH2CH2CH2CH2 OH H OSO2OH HOCH2CH2CH2CH2CH2 O OSO2OH H 1,5-Pentanediol Sulfuric acid Conjugate acid of 1,5-pentanediol Hydrogen sulfate Rewriting the alkyloxonium ion gives H HO CH2CH2CH2CH2CH2 O is equivalent to H H Forward Main Menu TOC Study Guide TOC O H Back O H Student OLC MHHE Website 367 ALCOHOLS, DIOLS, AND THIOLS The oxonium ion undergoes cyclization by intramolecular nucleophilic attack of its alcohol function on the carbon that bears the leaving group. H2O H O O O H H H Conjugate acid of 1,5-pentanediol Conjugate acid of oxane Water Loss of a proton gives oxane. OSO2OH H O OSO2OH O H Conjugate acid of oxane 15.8 (b) Sulfuric acid The relationship of the molecular formula of the ester (C10H10O4) to that of the starting dicarboxylic acid (C8H6O4) indicates that the diacid reacted with 2 moles of methanol to form a diester. O 2CH3OH Methanol 15.9 Oxane Hydrogen sulfate O O HOC COH H CH3OC 1,4-Benzenedicarboxylic acid O COCH3 Dimethyl 1,4-benzenedicarboxylate While neither cis- nor trans-4-tert-butylcyclohexanol is a chiral molecule, the stereochemical course of their reactions with acetic anhydride becomes evident when the relative stereochemistry of the ester function is examined for each case. The cis alcohol yields the cis acetate. O OH (CH3)3C CH3COCCH3 cis-4-tert-Butylcyclohexanol OCCH3 OO Acetic anhydride (CH3)3C cis-4-tert-Butylcyclohexyl acetate The trans alcohol yields the trans acetate. O OO OH (CH3)3C trans-4-tert-Butylcyclohexanol 15.10 CH3COCCH3 (CH3)3C Acetic anhydride trans-4-tert-Butylcyclohexyl acetate Glycerol has three hydroxyl groups, each of which is converted to a nitrate ester function in nitroglycerin. CH2OH CHOH CH2ONO2 3HNO3 H2SO4 CHONO2 CH2OH Forward Main Menu TOC CH2ONO2 Glycerol Back OCCH3 Nitroglycerin Study Guide TOC Student OLC MHHE Website 368 ALCOHOLS, DIOLS, AND THIOLS 15.11 (b) The substrate is a secondary alcohol and so gives a ketone on oxidation with sodium dichromate. 2-Octanone has been prepared in 92–96% yield under these reaction conditions. O CH3CH(CH2)5CH3 Na2Cr2O7 H2SO4, H2O CH3C(CH2)5CH3 OH 2-Octanol (c) 2-Octanone The alcohol is primary, and so oxidation can produce either an aldehyde or a carboxylic acid, depending on the reaction conditions. Here the oxidation is carried out under anhydrous conditions using pyridinium chlorochromate (PCC), and the product is the corresponding aldehyde. O CH3CH2CH2CH2CH2CH2CH2OH PCC CH2Cl2 CH3CH2CH2CH2CH2CH2CH 1-Heptanol 15.12 (b) Heptanal Biological oxidation of CH3CD2OH leads to loss of one of the C-1 deuterium atoms to NAD . The dihydropyridine ring of the reduced form of the coenzyme will bear a single deuterium. O CNH2 CH3CD2OH alcohol dehydrogenase O HD CNH2 CH3CD H N N R R 1,1-Dideuterioethanol (c) NAD 1-Deuterioethanal NADD The deuterium atom of CH3CH2OD is lost as D . The reduced form of the coenzyme contains no deuterium. O CNH2 CH3CH2OD alcohol dehydrogenase O HH CNH2 D N R R Ethanol-O-d (b) O CH3CH N 15.13 O NAD Ethanal NADH Oxidation of the carbon–oxygen bonds to carbonyl groups accompanies their cleavage. O (CH3)2CHCH2CH HIO4 CHCH2C6H5 OH (CH3)2CHCH2CH HCCH2C6H5 3-Methylbutanal 2-Phenylethanal OH 1-Phenyl-5-methyl-2,3-hexanediol (c) O The CH2OH group is cleaved from the ring as formaldehyde to leave cyclopentanone. O OH HIO4 O CH2OH 1-(Hydroxymethyl)cyclopentanol Back Forward Main Menu TOC HCH Cyclopentanone Study Guide TOC Formaldehyde Student OLC MHHE Website 369 ALCOHOLS, DIOLS, AND THIOLS 15.14 Thiols may be prepared from the corresponding alkyl halide by reaction with thiourea followed by treatment of the isothiouronium salt with base. RBr (H2N)2C Alkyl bromide S NaOH Isothiouronium salt (not isolated) Thiourea RSH Thiol Thus, an acceptable synthesis of 1-hexanethiol from 1-hexanol would be CH3(CH2)4CH2OH PBr3 HBr, heat 1-Hexanol 15.15 S CH3(CH2)4CH2SH 2. NaOH 1-Bromohexane 1-Hexanethiol The three main components of “essence of skunk” are H H3C CH3 C CH2SH H3C C C CH3CHCH2CH2SH H 3-Methyl-1-butanethiol 15.16 1. (H2N)2C CH3(CH2)4CH2Br CH2SH trans-2-Butene-1-thiol C H H cis-2-Butene-1-thiol The molecular weight of 2-methyl-2-butanol is 88. A peak in its mass spectrum at m z 70 corresponds to loss of water from the molecular ion. The peaks at m z 73 and m z 59 represent stable cations corresponding to the cleavages shown in the equation. OH CH3 C CH2CH3 CH3 OH CH3 OH (a) CH3CCH3 m /z 73 15.17 CH3CCH2CH3 m /z 59 The appropriate alkene for the preparation of 1-butanol by a hydroboration–oxidation sequence is 1-butene. Remember, hydroboration–oxidation leads to hydration of alkenes with a regioselectivity opposite to that seen in acid-catalyzed hydration. CH3CH2CH 1. B2H6 CH2 2. H2O2, HO CH3CH2CH2CH2OH 1-Butene (b) CH2CH3 1-Butanol 1-Butanol can be prepared by reaction of a Grignard reagent with formaldehyde. O CH3CH2CH2CH2OH CH3CH2CH2 HCH An appropriate Grignard reagent is propylmagnesium bromide. CH3CH2CH2Br Mg diethyl ether 1-Bromopropane CH3CH2CH2MgBr Propylmagnesium bromide O CH3CH2CH2MgBr HCH 1. diethyl ether 2. H3O CH3CH2CH2CH2OH 1-Butanol Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 370 ALCOHOLS, DIOLS, AND THIOLS (c) Alternatively, 1-butanol may be prepared by the reaction of a Grignard reagent with ethylene oxide. CH3CH2 CH3CH2CH2CH2OH H2C CH2 O In this case, ethylmagnesium bromide would be used. Mg CH3CH2Br CH3CH2MgBr diethyl ether Ethyl bromide Ethylmagnesium bromide H2C CH3CH2MgBr CH2 1. diethyl ether 2. H3O CH3CH2CH2CH2OH O Ethylene oxide (d ) 1-Butanol Primary alcohols may be prepared by reduction of the carboxylic acid having the same number of carbons. Among the reagents we have discussed, the only one that is effective in the reduction of carboxylic acids is lithium aluminum hydride. The four-carbon carboxylic acid butanoic acid is the proper substrate. O CH3CH2CH2COH 1. LiAlH4, diethyl ether 2. H2O CH3CH2CH2CH2OH Butanoic acid (e) 1-Butanol Reduction of esters can be accomplished using lithium aluminum hydride. The correct methyl ester is methyl butanoate. O 1. LiAlH4 CH3CH2CH2COCH3 CH3CH2CH2CH2OH CH3OH 1-Butanol 2. H2O Methanol Methyl butanoate (f ) A butyl ester such as butyl acetate may be reduced with lithium aluminum hydride to prepare 1-butanol. O 1. LiAlH4 CH3COCH2CH2CH2CH3 CH3CH2CH2CH2OH CH3CH2OH 1-Butanol 2. H2O Ethanol Butyl acetate (g) Because 1-butanol is a primary alcohol having four carbons, butanal must be the aldehyde that is hydrogenated. Suitable catalysts are nickel, palladium, platinum, and ruthenium. O CH3CH2CH2CH H2, Pt CH3CH2CH2CH2OH Butanal (h) 1-Butanol Sodium borohydride reduces aldehydes and ketones efficiently. It does not reduce carboxylic acids, and its reaction with esters is too slow to be of synthetic value. O CH3CH2CH2CH Butanal Back Forward Main Menu TOC NaBH4 water, ethanol, or methanol Study Guide TOC CH3CH2CH2CH2OH 1-Butanol Student OLC MHHE Website 371 ALCOHOLS, DIOLS, AND THIOLS 15.18 (a) Both (Z)- and (E)-2-butene yield 2-butanol on hydroboration–oxidation. CH3CH CHCH3 1. B2H6 CH3CHCH2CH3 2. H2O2, HO OH (Z )- or (E )-2-butene (b) 2-Butanol Disconnection of one of the bonds to the carbon that bears the hydroxyl group reveals a feasible route using a Grignard reagent and propanal. Disconnect this bond. H3C O CH3 CHCH2CH3 HCCH2CH3 OH Propanal The synthetic sequence is O Mg CH3Br 1. CH3CH2CH CH3MgBr diethyl ether CH3CHCH2CH3 2. H3O OH Methyl bromide (c) Methylmagnesium bromide 2-Butanol Another disconnection is related to a synthetic route using a Grignard reagent and acetaldehyde. Disconnect this bond. CH3CH O CH2CH3 CH3CH OH CH3C 2 CH Acetaldehyde O CH3CH2Br Mg diethyl ether CH3CH2MgBr 1. CH3CH 2. H3O CH3CH2CHCH3 OH Ethyl bromide Ethylmagnesium bromide 2-Butanol (d– f ) Because 2-butanol is a secondary alcohol, it can be prepared by reduction of a ketone having the same carbon skeleton, in this case 2-butanone. All three reducing agents indicated in the equations are satisfactory. O CH3CCH2CH3 H2, Pd (or Pt, Ni, Ru) CH3CHCH2CH3 OH 2-Butanone 2-Butanol O CH3CCH2CH3 NaBH4 CH3OH CH3CHCH2CH3 OH 2-Butanone 2-Butanol O CH3CCH2CH3 1. LiAlH4 2. H2O CH3CHCH2CH3 OH 2-Butanone Back Forward Main Menu TOC Study Guide TOC 2-Butanol Student OLC MHHE Website 372 ALCOHOLS, DIOLS, AND THIOLS 15.19 (a) All the carbon–carbon disconnections are equivalent. O CH3 H3C C CH3 OH CH3CCH3 CH3 Acetone The synthesis via a Grignard reagent and acetone is O Mg CH3Br Methyl bromide (b) CH3MgBr diethyl ether 1. CH3CCH3 (CH3)3COH 2. H3O Methylmagnesium bromide tert-Butyl alcohol An alternative route to tert-butyl alcohol is addition of a Grignard reagent to an ester. Esters react with 2 moles of Grignard reagent. Thus, tert-butyl alcohol may be formed by reacting methyl acetate with 2 moles of methylmagnesium iodide. Methyl alcohol is formed as a byproduct of the reaction. O 2CH3MgI CH3 CH3COCH3 1. diethyl ether 2. H3O CH3 C OH CH3OH CH3 Methylmagnesium iodide 15.20 (a) Methyl acetate tert-Butyl alcohol Methyl alcohol All of the primary alcohols having the molecular formula C5H12O may be prepared by reduction of aldehydes. The appropriate equations are O CH3CH2CH2CH2CH 1. LiAlH4, diethyl ether 2. H2O Pentanal CH3CH2CH2CH2CH2OH 1-Pentanol O CH3CH2CHCH 1. LiAlH4, diethyl ether 2. H2O CH3CH2CHCH2OH CH3 CH3 2-Methylbutanal 2-Methyl-1-butanol O (CH3)2CHCH2CH 1. LiAlH4, diethyl ether 2. H2O 3-Methylbutanal (CH3)2CHCH2CH2OH 3-Methyl-1-butanol O 1. LiAlH4, diethyl ether (CH3)3CCH 2. H2O 2,2-Dimethylpropanal Back Forward Main Menu TOC Study Guide TOC (CH3)3CCH2OH 2,2-Dimethyl-1-propanol Student OLC MHHE Website 373 ALCOHOLS, DIOLS, AND THIOLS (b) The secondary alcohols having the molecular formula C5H12O may be prepared by reduction of ketones. O OH 1. LiAlH4, diethyl ether CH3CH2CH2CCH3 2. H2O CH3CH2CH2CHCH3 2-Pentanone 2-Pentanol O OH 1. LiAlH4, diethyl ether CH3CH2CCH2CH3 2. H2O CH3CH2CHCH2CH3 3-Pentanone 3-Pentanol O OH 1. LiAlH4, diethyl ether (CH3)2CHCCH3 2. H2O 3-Methyl-2-butanone (c) (CH3)2CHCHCH3 3-Methyl-2-butanol As with the reduction of aldehydes in part (a), reduction of carboxylic acids yields primary alcohols. For example, 1-pentanol may be prepared by reduction of pentanoic acid. O 1. LiAlH4, diethyl ether CH3CH2CH2CH2COH 2. H2O CH3CH2CH2CH2CH2OH Pentanoic acid (d ) 1-Pentanol The remaining primary alcohols, 2-methyl-1-butanol, 3-methyl-1-butanol, and 2,2-dimethyl1-propanol, may be prepared in the same way. As with carboxylic acids, esters may be reduced using lithium aluminum hydride to give primary alcohols. For example, 2,2-dimethyl-1-propanol may be prepared by reduction of methyl 2,2-dimethylpropanoate. O 1. LiAlH4, diethyl ether (CH3)3CCOCH3 Methyl 2,2-dimethylpropanoate 15.21 (a) (CH3)3CCH2OH 2. H2O 2,2-Dimethyl-1-propanol The suggested synthesis CH3CH2CH2CH3 Br2 light or heat CH3CH2CH2CH2Br Butane KOH CH3CH2CH2CH2OH 1-Bromobutane 1-Butanol is a poor one because bromination of butane yields a mixture of 1-bromobutane and 2-bromobutane, 2-bromobutane being the major product. CH3CH2CH2CH3 Br2 light or heat CH3CH2CH2CH2Br CH3CHCH2CH3 Br Butane Back Forward Main Menu TOC 1-Bromobutane (minor product) Study Guide TOC Student OLC 2-Bromobutane (major product) MHHE Website 374 ALCOHOLS, DIOLS, AND THIOLS (b) The suggested synthesis Br2 (CH3)3CH light or heat 2-Methylpropane (c) (CH3)3COH 2-Bromo-2methylpropane 2-Methyl-2propanol will fail because the reaction of 2-bromo-2-methylpropane with potassium hydroxide will proceed by elimination rather than by substitution. The first step in the process, selective bromination of 2-methylpropane to 2-bromo-2-methylpropane, is satisfactory because bromination is selective for substitution of tertiary hydrogens in the presence of secondary and primary ones. Benzyl alcohol, unlike 1-butanol and 2-methyl-2-propanol, can be prepared effectively by this method. Br2 CH3 KOH CH2Br light or heat Toluene (d ) KOH (CH3)3CBr CH2OH Benzyl bromide Benzyl alcohol Free-radical bromination of toluene is selective for the benzylic position. Benzyl bromide cannot undergo elimination, and so nucleophilic substitution of bromide by hydroxide will work well. The desired transformation CH2CH3 Br2 KOH CHCH3 light or heat CHCH3 Br Ethylbenzene OH 1-Bromo-1-phenylethane 1-Phenylethanol fails because it produces more than one enantiomer. The reactant ethylbenzene is achiral and although its bromination will be highly regioselective for the benzylic position, the product will be a racemic mixture of (R) and (S)-1-bromo-1-phenylethane. The alcohol produced by hydrolysis will also be racemic. Furthermore, the hydrolysis step will give mostly styrene by an E2 elimination, rather than 1-phenylethanol by nucleophilic substitution. 15.22 Glucose contains five hydroxyl groups and an aldehyde functional group. Its hydrogenation will not affect the hydroxyl groups but will reduce the aldehyde to a primary alcohol. OH OH O OH OH H2 (120 atm) HO H HO OH Ni, 140 C OH OH OH OH Glucose 15.23 (a) Sorbitol 1-Phenylethanol is a secondary alcohol and so can be prepared by the reaction of a Grignard reagent with an aldehyde. One combination is phenylmagnesium bromide and ethanal (acetaldehyde). O C6H5CHCH3 C6 H5 MgBr HCCH3 Phenylmagnesium bromide Ethanal (acetaldehyde) OH 1-Phenylethanol Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 375 ALCOHOLS, DIOLS, AND THIOLS Grignard reagents—phenylmagnesium bromide in this case—are always prepared by reaction of magnesium metal and the corresponding halide. Starting with bromobenzene, a suitable synthesis is described by the sequence O Mg C6 H5 Br 1. CH3CH C6H5MgBr diethyl ether C6 H5 CHCH3 2. H3O OH Bromobenzene (b) Phenylmagnesium bromide 1-Phenylethanol An alternative disconnection of 1-phenylethanol reveals a second route using benzaldehyde and a methyl Grignard reagent. O C6H5CHCH3 C6H5CH CH3MgI Benzaldehyde Methylmagnesium iodide OH 1-Phenylethanol Equations representing this approach are O CH3I Mg 1. C6H5CH CH3MgI diethyl ether 2. H3O C6H5CHCH3 OH Iodomethane (c) Methylmagnesium iodide 1-Phenylethanol Aldehydes are, in general, obtainable by oxidation of the corresponding primary alcohol. By recognizing that benzaldehyde can be obtained by oxidation of benzyl alcohol with PCC, we write O C6H5CH2OH PCC CH2Cl2 C6H5CH 1. CH3MgI, diethyl ether 2. H3O C6H5CHCH3 OH Benzyl alcohol (d ) Benzaldehyde 1-Phenylethanol The conversion of acetophenone to 1-phenylethanol is a reduction. O C6H5CCH3 reducing agent C6H5CHCH3 OH Acetophenone 1-Phenylethanol Any of a number of reducing agents could be used. These include 1. NaBH4, CH3OH 2. LiAlH4 in diethyl ether, then H2O 3. H2 and a Pt, Pd, Ni, or Ru catalyst Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 376 ALCOHOLS, DIOLS, AND THIOLS (e) Benzene can be employed as the ultimate starting material in a synthesis of 1-phenylethanol. Friedel–Crafts acylation of benzene gives acetophenone, which can then be reduced as in part (d ). O O CH3CCl Benzene AlCl3 CCH3 Acetyl chloride Acetophenone OO Acetic anhydride (CH3COCCH3) can be used in place of acetyl chloride. 15.24 2-Phenylethanol is an ingredient in many perfumes, to which it imparts a rose-like fragrance. Numerous methods have been employed for its synthesis. (a) As a primary alcohol having two more carbon atoms than bromobenzene, it can be formed by reaction of a Grignard reagent, phenylmagnesium bromide, with ethylene oxide. O C6 H5CH2CH2OH C6H5MgBr H2C CH2 The desired reaction sequence is therefore CH2 1. H2C Mg C6H5Br C6H5MgBr diethyl ether Bromobenzene (b) O 2. H3O Phenylmagnesium bromide 2-Phenylethanol Hydration of sytrene with a regioselectivity contrary to that of Markovnikov’s rule is required. This is accomplished readily by hydroboration–oxidation. C6H5CH CH2 1. B2H6, diglyme 2. H2O2, HO C6H5CH2CH2OH Styrene (c) C6H5CH2CH2OH 2-Phenylethanol Reduction of aldehydes yields primary alcohols. O C6 H5 CH2CH reducing agent 2-Phenylethanal (d ) C6 H5 CH2CH2OH 2-Phenylethanol Among the reducing agents that could be (and have been) used are 1. NaBH4, CH3OH 2. LiAlH4 in diethyl ether, then H2O 3. H2 and a Pt, Pd, Ni, or Ru catalyst Esters are readily reduced to primary alcohols with lithium aluminum hydride. O C6H5CH2COCH2CH3 1. LiAlH4, diethyl ether 2. H2O Ethyl 2-phenylethanoate Back Forward Main Menu TOC Study Guide TOC C6 H5 CH2CH2OH 2-Phenylethanol Student OLC MHHE Website 377 ALCOHOLS, DIOLS, AND THIOLS (e) The only reagent that is suitable for the direct reduction of carboxylic acids to primary alcohols is lithium aluminum hydride. O 1. LiAlH4, diethyl ether C6H5CH2COH C6H5CH2CH2OH 2. H2O 2-Phenylethanoic acid 2-Phenylethanol Alternatively, the carboxylic acid could be esterified with ethanol and the resulting ethyl 2-phenylethanoate reduced. O O C6H5CH2COH CH3CH2OH 2-Phenylethanoic acid H Ethanol 15.25 (a) C6H5CH2COCH2CH3 C6H5CH2CH2OH Ethyl 2-phenylethanoate 2-Phenylethanol Thiols are made from alkyl halides by reaction with thiourea, followed by hydrolysis of the isothiouronium salt in base. The first step must therefore be a conversion of the alcohol to an alkyl bromide. HBr CH3CH2CH2CH2OH or PBr3 1. (H2N)2C CH3CH2CH2CH2Br 1-Butanol (b) reduce as in part (d ) S CH3CH2CH2CH2SH 2. NaOH 1-Bromobutane 1-Butanethiol To obtain 1-hexanol from alcohols having four carbons or fewer, a two-carbon chain extension must be carried out. This suggests reaction of a Grignard reagent with ethylene oxide. The retrosynthetic path for this approach is O CH3CH2CH2CH2 CH2CH2OH CH3CH2CH2CH2MgBr H2C CH2 The reaction sequence therefore becomes 1. H2C CH3CH2CH2CH2Br Mg CH3CH2CH2CH2MgBr diethyl ether 1-Bromobutane from part (a) CH2 O CH3CH2CH2CH2CH2CH2OH 2. H3O Butylmagnesium bromide 1-Hexanol Given the constraints of the problem, we prepare ethylene oxide by the sequence O CH3CH2OH H2SO4 heat Ethanol (c) H2C CH2 CH3COOH H2C CH2 O Ethylene The target molecule 2-hexanol may be mentally disconnected as shown to a four-carbon unit and a two-carbon unit. O CH3CH CH2CH2CH2CH3 CH3CH CH2CH2CH2CH3 OH Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 378 ALCOHOLS, DIOLS, AND THIOLS O The alternative disconnection to :CH3 and HCCH2CH2CH2CH3 reveals a plausible approach to 2-hexanol but is inconsistent with the requirement of the problem that limits starting materials to four carbons or fewer. The five-carbon aldehyde would have to be prepared first, making for a lengthy overall synthetic scheme. An appropriate synthesis based on alcohols as starting materials is O PCC CH2Cl CH3CH2OH CH3CH Ethanol Ethanal O CH3CH2CH2CH2MgBr Butylmagnesium bromide from part (b) 1. diethyl ether CH3CH CH3CHCH2CH2CH2CH3 Ethanal 2. H3O OH (d ) 2-Hexanol Hexanal may be obtained from 1-hexanol [prepared in part (b)] by oxidation in dichloromethane using pyridinium chlorochromate (PCC) or pyridinium dichromate (PDC). O CH3(CH2)4CH2OH PCC or PDC CH2Cl2 CH3(CH2)4CH 1-Hexanol from part (b) (e) Hexanal Oxidation of 2-hexanol from part (c) yields 2-hexanone. O CH3CHCH2CH2CH2CH3 Na2Cr2O7 H2SO4, H2O CH3CCH2CH2CH2CH3 OH 2-Hexanol (f) 2-Hexanone PCC or PDC can also be used for this transformation. Oxidation of 1-hexanol with chromic acid (sodium or potassium dichromate in aqueous sulfuric acid) yields hexanoic acid. Use of PDC or PCC in dichloromethane is not acceptable because those reagents yield aldehydes on reaction with primary alcohols. CH3(CH2)4CH2OH K2Cr2O7 H2SO4, H2O CH3(CH2)4CO2H 1-Hexanol from part (b) (g) Hexanoic acid Fischer esterification of hexanoic acid with ethanol produces ethyl hexanoate. O CH3(CH2)4CO2H Hexanoic acid from part ( f ) (h) CH3CH2OH H Ethanol Ethyl hexanoate Vicinal diols are normally prepared by hydroxylation of alkenes with osmium tetraoxide and tert-butyl hydroperoxide. (CH3)2C CH2 OsO4 (CH3)3COOH, HO (CH3)3COH 2-Methylpropene Back Forward CH3(CH2)4COCH2CH3 Main Menu TOC Study Guide TOC (CH3)2CCH2OH OH 2-Methyl-1,2propanediol Student OLC MHHE Website 379 ALCOHOLS, DIOLS, AND THIOLS The required alkene is available by dehydration of 2-methyl-2-propanol. H3PO4 (CH3)3COH (CH3)2C heat 2-Methyl-2-propanol (i) CH2 2-Methylpropene The desired aldehyde can be prepared by oxidation of the corresponding primary alcohol with PCC or PDC. O PCC or PDC CH2Cl2 (CH3)3CCH2OH (CH3)3CCH 2,2-Dimethyl-1-propanol 2,2-Dimethylpropanal The necessary alcohol is available through reaction of a tert-butyl Grignard reagent with formaldehyde, as shown by the disconnection (CH3)3CCH2OH (CH3)3CMgCl H2C O O PCC or PDC CH2Cl2 CH3OH HCH Methanol HCl (CH3)3COH Formaldehyde Mg (CH3)3CCl 2-Methyl-2-propanol (tert-butyl alcohol) diethyl ether 2-Chloro2-methylpropane (tert-butyl chloride) 1. H2C (CH3)3CMgCl 1,1-Dimethylethylmagnesium chloride (tert-butylmagnesium chloride) O, diethyl ether (CH3)3CCH2OH 2. H3O 1,1-Dimethylethylmagnesium chloride (tert-butylmagnesium chloride) 15.26 (a) (CH3)3CMgCl 2,2-Dimethyl-1-propanol The simplest route to this primary chloride from benzene is through the corresponding alcohol. The first step is the two-carbon chain extension used in Problem 15.24a. Br Br2 CH2CH2OH 1. Mg, diethyl ether FeBr3 2. H2C CH2 O 3. H3O Benzene Bromobenzene CH2CH2OH 2-Phenylethanol CH2CH2Cl SOCl2 2-Phenylethanol 1-Chloro-2-phenylethane The preparation of ethylene oxide is shown in Problem 15.25b. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 380 ALCOHOLS, DIOLS, AND THIOLS (b) A Friedel–Crafts acylation is the best approach to the target ketone. O O (CH3)2CHCCl Benzene CCH(CH3)2 AlCl3 2-Methylpropanoyl chloride 2-Methyl-1-phenyl-1propanone Because carboxylic acid chlorides are prepared from the corresponding acids, we write O (CH3)2CHCH2OH K2Cr2O7 (CH3)2CHCOH H2SO4, heat 2-Methyl-1-propanol (c) O SOCl2 (CH3)2CHCCl 2-Methylpropanoic acid 2-Methylpropanoyl chloride Wolff–Kishner or Clemmensen reduction of the ketone just prepared in part (b) affords isobutylbenzene. O H2NNH2, HO triethylene glycol, heat C6H5CCH(CH3)2 or Zn(Hg), HCl 2-Methyl-1-phenyl-1-propanone C6H5CH2CH(CH3)2 Isobutylbenzene A less direct approach requires three steps: O NaBH4 C6H5CCH(CH3)2 H2SO4 C6H5CHCH(CH3)2 CH3OH C6H5CH heat C(CH3)2 H2 C6H5CH2CH(CH3)2 Pt OH 2-Methyl-1-phenyl-1propanone 2-Methyl-1-phenyl-1propanol 15.27 (a) 2-Methyl-1phenylpropene Isobutylbenzene Because 1-phenylcyclopentanol is a tertiary alcohol, a likely synthesis would involve reaction of a ketone and a Grignard reagent. Thus, a reasonable last step is treatment of cyclopentanone with phenylmagnesium bromide. 1. C6H5MgBr, diethyl ether OH 2. H3O O C6H5 Cyclopentanone 1-Phenylcyclopentanol Cyclopentanone is prepared by oxidation of cyclopentanol. Any one of a number of oxidizing agents would be suitable. These include PDC or PCC in CH2Cl2 or chromic acid (H2CrO4) generated from Na2Cr2O7 in aqueous sulfuric acid. OH oxidize H Cyclopentanol (b) Cyclopentanone Acid-catalyzed dehydration of 1-phenylcyclopentanol gives 1-phenylcyclopentene. OH C6H5 H2SO4, heat or H3PO4, heat 1-Phenylcyclopentanol Back Forward O Main Menu TOC Study Guide TOC C6H5 1-Phenylcyclopentene Student OLC MHHE Website 381 ALCOHOLS, DIOLS, AND THIOLS (c) Hydroboration–oxidation of 1-phenylcyclopentene gives trans-2-phenylcyclopentanol. The elements of water (H and OH) are added across the double bond opposite to Markovnikov’s rule and syn to each other. HO H H H 1. B2H6, diglyme C6H5 2. H2O2, HO C6H5 1-Phenylcyclopentene (d ) trans -2-Phenylcyclopentanol Oxidation of trans-2-phenylcyclopentanol converts this secondary alcohol to the desired ketone. Any of the Cr(VI)-derived oxidizing agents mentioned in part (a) for oxidation of cyclopentanol to cyclopentanone is satisfactory. HO H O H H Cr(VI) oxidation C6H5 C6H5 trans -2-Phenylcyclopentanol (e) 2-Phenylcyclopentanone The standard procedure for preparing cis-1,2-diols is by hydroxylation of alkenes with osmium tetraoxide. HO H H OsO4, (CH3)3COOH OH (CH3)3COH, HO C6H5 C6H5 1-Phenylcyclopentene (f ) 1-Phenyl-cis-1,2-cyclopentanediol The desired compound is available either by ozonolysis of 1-phenylcyclopentene: H O 1. O3 C6H5 O C6H5CCH2CH2CH2CH 2. H2O, Zn 1-Phenylcyclopentene 5-Oxo-1-phenyl-1-pentanone or by periodic acid cleavage of the diol in part (e): HO H OH O HIO4 C6H5 1-Phenyl-cis-1,2cyclopentanediol (g) O C6H5CCH2CH2CH2CH 5-Oxo-1-phenyl-1-pentanone H2, Pt (or Pd, Ni, Ru) or NaBH4, H2O or 1. LiAlH4, diethyl ether 2. H2O 5-Oxo-1-phenyl-1-pentanone Forward C6H5CCH2CH2CH2CH Reduction of both carbonyl groups in the product of part ( f ) gives the desired diol. O Back O Main Menu TOC Study Guide TOC C6H5CHCH2CH2CH2CH2OH OH 1-Phenyl-1,5-pentanediol Student OLC MHHE Website 382 ALCOHOLS, DIOLS, AND THIOLS 15.28 (a, b) Primary alcohols react in two different ways on being heated with acid catalysts: they can condense to form dialkyl ethers or undergo dehydration to yield alkenes. Ether formation is favored at lower temperature, and alkene formation is favored at higher temperature. H2SO4 2CH3CH2CH2OH CH3CH2CH2OCH2CH2CH3 H2O Dipropyl ether 140°C Water 1-Propanol CH3CH2CH2OH H2SO4 CH3CH 200°C 1-Propanol (c) H2O Propene Water Nitrate esters are formed by the reaction of alcohols with nitric acid in the presence of a sulfuric acid catalyst. CH3CH2CH2OH H2SO4(cat) HONO2 1-Propanol (d ) CH2 CH3CH2CH2ONO2 Nitric acid H2O Propyl nitrate Water Pyridinium chlorochromate (PCC) oxidizes primary alcohols to aldehydes. O CH3CH2CH2OH PCC CH2Cl2 CH3CH2CH 1-Propanol (e) Propanal Potassium dichromate in aqueous sulfuric acid oxidizes primary alcohols to carboxylic acids. O K2Cr2O7 CH3CH2CH2OH 1-Propanol (f) CH3CH2COH H2SO4, H2O heat Propanoic acid Amide ion, a strong base, abstracts a proton from 1-propanol to form ammonia and 1-propanolate ion. This is an acid–base reaction. CH3CH2CH2OH CH3CH2CH2ONa NH3 1-Propanol (g) NaNH2 Sodium amide Sodium 1-propanolate Ammonia With acetic acid and in the presence of an acid catalyst, 1-propanol is converted to its acetate ester. O CH3CH2CH2OH 1-Propanol (h) CH3COH O HCl CH3COCH2CH2CH3 Acetic acid H2O Propyl acetate Water This is an equilibrium process that slightly favors products. Alcohols react with p-toluenesulfonyl chloride to give p-toluenesulfonate esters. O CH3CH2CH2OH CH3 SO2Cl pyridine CH3CH2CH2OS CH3 HCl O 1-Propanol Back Forward Main Menu p-Toluenesulfonyl chloride TOC Study Guide TOC Propyl p-toluenesulfonate Student OLC MHHE Website 383 ALCOHOLS, DIOLS, AND THIOLS (i) Acyl chlorides convert alcohols to esters. O CH3CH2CH2OH 1-Propanol ( j) CH3O CCl CH3CH2CH2OC p-Methoxybenzoyl chloride OCH3 HCl Propyl p-methoxybenzoate The reagent is benzoic anhydride. Carboxylic acid anhydrides react with alcohols to give esters. OO O O CH3CH2CH2OH pyridine C6H5COCC6H5 1-Propanol (k) O pyridine CH3CH2CH2OCC6H5 C6H5COH Propyl benzoate Benzoic acid Benzoic anhydride The reagent is succinic anhydride, a cyclic anhydride. Esterification occurs, but in this case the resulting ester and carboxylic acid functions remain part of the same molecule. O O pyridine O CH3CH2CH2OH O CH3CH2CH2OCCH2CH2COH O 1-Propanol 15.29 (a) Succinic anhydride Hydrogen propyl succinate On being heated in the presence of sulfuric acid, tertiary alcohols undergo elimination. C6H5 H3C H2SO4 H3C heat OH 4-Methyl-1phenylcyclohexanol (b) C6H5 4-Methyl-1phenylcyclohexene (81%) The combination of reagents specified converts alkenes to vicinal diols. (CH3)2C C(CH3)2 (CH3)3COOH, OsO4(cat) (CH3)3COH, HO (CH3)2C HO 2,3-Dimethyl-2-butene (c) C(CH3)2 OH 2,3-Dimethyl-2,3-butanediol (72%) Hydroboration–oxidation of the double bond takes place with a regioselectivity that is opposite to Markovnikov’s rule. The elements of water are added in a stereospecific syn fashion. H HO C6H5 C6H5 1. B2H6, diglyme 2. H2O2, HO 1-Phenylcyclobutene (d ) trans-2-Phenylcyclobutanol (82%) Lithium aluminum hydride reduces carboxylic acids to primary alcohols, but does not reduce carbon–carbon double bonds. CO2H 1. LiAlH4, diethyl ether 2. H2O Cyclopentene-4carboxylic acid Back Forward Main Menu TOC Study Guide TOC CH2OH (3-Cyclopentenyl)methanol Student OLC MHHE Website 384 ALCOHOLS, DIOLS, AND THIOLS (e) Chromic acid oxidizes the secondary alcohol to the corresponding ketone but does not affect the triple bond. O CH3CHC C(CH2)3CH3 OH H2CrO4 H2SO4, H2O acetone CH3CC 3-Octyn-2-ol (f ) C(CH2)3CH3 3-Octyn-2-one (80%) Lithium aluminum hydride reduces carbonyl groups efficiently but does not normally react with double bonds. O O CH3CCH2CH 1. LiAlH4, diethyl ether CHCH2CCH3 CH3CHCH2CH 2. H2O CHCH2CHCH3 OH OH 4-Octen-2,7-dione (g) 4-Octen-2,7-diol (75%) Alcohols react with acyl chlorides to yield esters. The O @ H bond is broken in this reaction; the C @ O bond of the alcohol remains intact on ester formation. NO2 O O2N OH O CCl H3C OC pyridine H 3C NO2 O2N trans-3-Methylcyclohexanol (h) 3,5-Dinitrobenzoyl chloride trans-3-Methylcyclohexyl-3,5dinitrobenzoate (74%) Carboxylic acid anhydrides react with alcohols to give esters. Here, too, the spatial orientation of the C @ O bond remains intact. O OO OH O CH3COCCH3 OCCH3 H H exo-Bicyclo[2.2.1]heptan-2-ol (i) Acetic anhydride exo-Bicyclo[2.2.1]hept2-yl acetate (90%) Cl O2N O COH CH3OH H2SO4 O2N Main Menu TOC O COCH3 Cl O2N 4-Chloro-3,5dinitrobenzoic acid Forward Acetic acid The substrate is a carboxylic acid and undergoes Fischer esterification with methanol. O2N Back CH3COH Study Guide TOC Methyl 4-chloro-3,5dinitrobenzoate (96%) Student OLC MHHE Website 385 ALCOHOLS, DIOLS, AND THIOLS ( j) Both ester functions are cleaved by reduction with lithium aluminum hydride. The product is a diol. O CH3CO H3C O HO CH2OH COCH3 1. LiAlH4 H3C CH3CH2OH 2. H2O CH3OH (96%) (k) Treatment of the diol obtained in part ( j) with periodic acid brings about its cleavage to two carbonyl compounds. O HO CH2OH H3C O H3C HIO4 HCH (74%) 15.30 Only the hydroxyl groups on C-1 and C-4 can be involved, since only these two can lead to a fivemembered cyclic ether. HO HOCH2CHCH2CH2OH H heat H2O O OH 1,2,4-Butanetriol 3-Hydroxyoxolane (C4H8O2) Any other combination of hydroxyl groups would lead to a strained three-membered or fourmembered ring and is unfavorable under conditions of acid catalysis. 15.31 Hydroxylation of alkenes with osmium tetraoxide is a syn addition. A racemic mixture of the 2R,3S and 2S,3R stereoisomers is formed from cis-2-pentene. OH H CH2CH3 H CH2CH3 H OsO4, (CH3)3COOH (CH3)3COH, HO CH3 OH CH3 H H HO H OH cis-2-Pentene 2S,3R-2,3-Pentanediol CH2CH3 CH3 2R,3S-2,3-Pentanediol trans-2-Pentene gives a racemic mixture of the 2R,3R and 2S,3S stereoisomers. OH H CH2CH3 H3C trans-2-Pentene Back Forward Main Menu OsO4, (CH3)3COOH (CH3)3COH, HO H TOC CH2CH3 H H3C OH H OH H HO H3C 2R,3R-2,3-Pentanediol Study Guide TOC Student OLC CH2CH3 H 2S,3S-2,3-Pentanediol MHHE Website 386 ALCOHOLS, DIOLS, AND THIOLS 15.32 (a) The task of converting a ketone to an alkene requires first the reduction of the ketone to an alcohol and then dehydration. In practice the two-step transformation has been carried out in 54% yield by treating the ketone with sodium borohydride and then heating the resulting alcohol with p-toluenesulfonic acid. NaBH4 CH3OH O (b) H heat OH Of course, sodium borohydride may be replaced by other suitable reducing agents, and p-toluenesulfonic acid is not the only acid that could be used in the dehydration step. This problem and the next one illustrate the value of reasoning backward. The desired product, cyclohexanol, can be prepared cleanly from cyclohexanone. OH OH CH2OH O Once cyclohexanone is recognized to be a key intermediate, the synthetic pathway becomes apparent—what is needed is a method to convert the indicated starting material to cyclohexanone. The reagent ideally suited to this task is periodic acid. The synthetic sequence to be followed is therefore OH CH2OH HIO4 O OH NaBH4 CH3OH 1-(Hydroxymethyl)cyclohexanol (c) Cyclohexanone Cyclohexanol No direct method allows a second hydroxyl group to be introduced at C-2 of 1-phenylcyclohexanol in a single step. We recognize the product as a vicinal diol and recall that such compounds are available by hydroxylation of alkenes. OH C6H5 OH C6H5 C6H5 OH This tells us that we must first dehydrate the tertiary alcohol, then hydroxylate the resulting alkene. OH C6H5 H2SO4 C6H5 heat OH C6H5 (CH3)3COOH (CH3)3COH OsO4, HO OH 1-Phenylcyclohexanol 1-Phenylcyclohexene 1-Phenyl-cis-1,2cyclohexanediol The syn stereoselectivity of the hydroxylation step ensures that the product will have its hydroxyl groups cis, as the problem requires. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 387 ALCOHOLS, DIOLS, AND THIOLS 15.33 Because the target molecule is an eight-carbon secondary alcohol and the problem restricts our choices of starting materials to alcohols of five carbons or fewer, we are led to consider building up the carbon chain by a Grignard reaction. O CH3 CH3CH2CH CHCH2CH2CH3 CH3 CH3CH2CH CHCH2CH2CH3 OH 4-Methyl-3-heptanol The disconnection shown leads to a three-carbon aldehyde and a five-carbon Grignard reagent. Starting with the corresponding alcohols, the following synthetic scheme seems reasonable. First, propanal is prepared. O PCC or PDC CH2Cl2 CH3CH2CH2OH CH3CH2CH 1-Propanol Propanal After converting 2-pentanol to its bromo derivative, a solution of the Grignard reagent is prepared. CH3CHCH2CH2CH3 PBr3 OH CH3CHCH2CH2CH3 Mg CH3CHCH2CH2CH3 diethyl ether Br 2-Pentanol MgBr 2-Bromopentane 1-Methylbutylmagnesium bromide Reaction of the Grignard reagent with the aldehyde yields the desired 4-methyl-3-heptanol. O CH3CHCH2CH2CH3 1. diethyl ether CH3CH2CH 2. H3O MgBr HOCHCH2CH3 1-Methylbutylmagnesium bromide 15.34 CH3CHCH2CH2CH3 Propanal 4-Methyl-3-heptanol Our target molecule is void of functionality and so requires us to focus attention on the carbon skeleton. Notice that it can be considered to arise from three ethyl groups. CH3 CH3CH2 CH CH2CH3 3-Methylpentane Considering the problem retrosynthetically, we can see that a key intermediate having the carbon skeleton of the desired product is 3-methyl-3-pentanol. This becomes apparent from the fact that alkanes may be prepared from alkenes, which in turn are available from alcohols. The desired alcohol may be prepared from reaction of an acetate ester with a Grignard reagent, ethylmagnesium bromide. CH3 CH3 CH3CH2CHCH2CH3 CH3CH2CCH2CH3 O CH3COR 2CH3CH2MgBr OH Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 388 ALCOHOLS, DIOLS, AND THIOLS The carbon skeleton can be assembled in one step by the reaction of ethylmagnesium bromide and ethyl acetate. O 2CH3CH2MgBr OH 1. diethyl ether CH3COCH2CH3 CH3CCH2CH3 2. H3O CH2CH3 Ethylmagnesium bromide Ethyl acetate 3-Methyl-3-pentanol The resulting tertiary alcohol is converted to the desired hydrocarbon by acid-catalyzed dehydration and catalytic hydrogenation of the resulting mixture of alkenes. OH H CH3CCH2CH3 CH3C CH2CH3 CHCH3 H2C C(CH2CH3)2 CH2CH3 3-Methyl-3-pentanol 2-Ethyl-1-butene 3-Methyl-2-pentene (cis trans) H2, Ni CH3CH(CH2CH3)2 3-Methylpentane Because the problem requires that ethanol be the ultimate starting material, we need to show the preparation of the ethylmagnesium bromide and ethyl acetate used in constructing the carbon skeleton. PBr3 CH3CH2OH CH3CH2Br Ethanol Mg CH3CH2MgBr diethyl ether Ethyl bromide Ethylmagnesium bromide O CH3CH2OH K2Cr2O7 CH3COH H2SO4, H2O, heat Ethanol Acetic acid O O CH3COH CH3CH2OH H+ CH3COCH2CH3 Acetic acid 15.35 (a) Retrosynthetically, we can see that the cis carbon–carbon double bond is available by hydrogenation of the corresponding alkyne over the Lindlar catalyst. CH3CH2CH Back Forward Ethyl acetate Main Menu CHCH2CH2OH TOC CH3CH2C Study Guide TOC CCH2CH2OH Student OLC MHHE Website 389 ALCOHOLS, DIOLS, AND THIOLS The @ CH2CH2OH unit can be appended to an alkynide anion by reaction with ethylene oxide. CH3CH2C CCH2CH2OH H2C C CH3CH2C CH2 O The alkynide anion is derived from 1-butyne by alkylation of acetylene. This analysis suggests the following synthetic sequence: HC CH 1. NaNH2, NH3 CH3CH2C 2. CH3CH2Br CH 1. NaNH2, NH3 2. H2C CH3CH2C CH2 CCH2CH2OH O Acetylene 1-Butyne 3-Hexyn-1-ol Lindlar Pd H2 CH3CH2 CH2CH2OH C C H H cis -3-Hexen-1-ol (b) The compound cited is the aldehyde derived by oxidation of the primary alcohol in part (a). Oxidize the alcohol with PDC or PCC in CH2Cl2. O CH3CH2 CH2CH2OH C C PDC or PCC in CH2Cl2 CH3CH2 H H C H H cis -3-Hexen-1-ol 15.36 CH2CH C cis -3-Hexenal Even though we are given the structure of the starting material, it is still better to reason backward from the target molecule rather than forward from the starting material. The desired product contains a cyano (@ CN) group. The only method we have seen so far for introducing such a function into a molecule is by nucleophilic substitution. The last step in the synthesis must therefore be CH2CN CH2X X CN OCH3 OCH3 This step should work very well, since the substrate is a primary benzylic halide, cannot undergo elimination, and is very reactive in SN2 reactions. The primary benzylic halide can be prepared from the corresponding alcohol by any of a number of methods. CH2OH OCH3 CH2X OCH3 Suitable reagents include HBr, PBr3, or SOCl2. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 390 ALCOHOLS, DIOLS, AND THIOLS Now we only need to prepare the primary alcohol from the given starting aldehyde, which is accomplished by reduction. O CH2OH CH OCH3 OCH3 Reduction can be achieved by catalytic hydrogenation, with lithium aluminum hydride, or with sodium borohydride. The actual sequence of reactions as carried out is as shown. O CH2OH CH H2, Pt CH2Br CH2CN HBr, benzene (98% yield) ethanol (100% yield) NaCN ethanol, water (87% yield) OCH3 OCH3 m-Methoxybenzaldehyde OCH3 m-Methoxybenzyl alcohol OCH3 m-Methoxybenzyl bromide m-Methoxybenzyl cyanide Another three-step synthesis, which is reasonable but does not involve an alcohol as an intermediate, is O CH3 CH Clemmensen CH2Br N-bromosuccinimide h or Wolff–Kishner reduction OCH3 OCH3 OCH3 m-Methoxybenzaldehyde 15.37 m-Methoxytoluene (a) CH2CN CN OCH3 m-Methoxybenzyl bromide m-Methoxybenzyl cyanide Addition of hydrogen chloride to cyclopentadiene takes place by way of the most stable carbocation. In this case it is an allylic carbocation. HCl not (Allylic carbocation; more stable) (Not allylic; less stable) Cl Cl 3-Chlorocyclopentene (80 –90%) (Compound A) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 391 ALCOHOLS, DIOLS, AND THIOLS Hydrolysis of 3-chlorocyclopentene gives the corresponding alcohol. Sodium bicarbonate in water is a weakly basic solvolysis medium. NaHCO3 H2 O Cl OH Compound A 2-Cyclopenten-1-ol (88%) (compound B) Oxidation of compound B (a secondary alcohol) gives the ketone 2-cyclopenten-1-one. Na 2Cr2O7 H2SO4, H2O O OH 2-Cyclopenten-1-one (60–68%) (compound C) Compound B (b) Thionyl chloride converts alcohols to alkyl chlorides. H2C CHCH2CH2CHCH3 SOCl2 H2C pyridine CHCH2CH2CHCH3 OH Cl 5-Hexen-2-ol 5-Chloro-1-hexene (compound D) Ozonolysis cleaves the carbon–carbon double bond. O H2C CHCH2CH2CHCH3 1. O3 2. reductive workup O HCCH2CH2CHCH3 Cl HCH Cl Compound D 4-Chloropentanal (compound E) Formaldehyde Reduction of compound E yields the corresponding alcohol. O HCCH2CH2CHCH3 NaBH4 HOCH2CH2CH2CHCH3 Cl Cl 4-Chloropentanal (c) 4-Chloro-1-pentanol (compound F) N-Bromosuccinimide is a reagent designed to accomplish benzylic bromination. CH3 NBS benzoyl peroxide, heat Br 1-Bromo-2-methylnaphthalene Back Forward Main Menu TOC Study Guide TOC CH2Br Br 1-Bromo-2-(bromomethyl)naphthalene (compound G) Student OLC MHHE Website 392 ALCOHOLS, DIOLS, AND THIOLS Hydrolysis of the benzylic bromide gives the corresponding benzylic alcohol. The bromine that is directly attached to the naphthalene ring does not react under these conditions. H2O, CaCO3 heat CH2OH CH2Br Br Br 1-Bromo-2-(bromomethyl)naphthalene (1-Bromo-2-naphthyl)methanol (compound H) Oxidation of the primary alcohol with PCC gives the aldehyde. PCC CH2Cl2 CH2OH CH Br Br (1-Bromo-2-naphthyl)methanol 15.38 O 1-Bromonaphthalene-2-carboxaldehyde (compound I) The alcohol is tertiary and benzylic and yields a relatively stable carbocation. CH3 C CH3 H2SO4 CH2CH3 C CH2CH3 OH 2-Phenyl-2-butanol 1-Methyl-1-phenylpropyl cation The alcohol is chiral, but the carbocation is not. Thus, irrespective of which enantiomer of 2-phenyl2-butanol is used, the same carbocation is formed. The carbocation reacts with ethanol to give an optically inactive mixture containing equal quantities of enantiomers (racemic). CH3 CH3 C CH3CH2OH C CH2CH3 1-Methyl-1-phenylpropyl cation 15.39 CH2CH3 H OCH2CH3 Ethanol 2-Ethoxy-2-phenylbutane (50% R, 50% S ) The difference between the two ethers is that 1-O-benzylglycerol contains a vicinal diol function, but 2-O-benzylglycerol does not. Periodic acid will react with 1-O-benzylglycerol but not with 2-Obenzylglycerol. O C6H5CH2OCH2CHCH2OH HIO4 O C6H5CH2OCH2CH HCH 2-Benzyloxyethanal Formaldehyde OH 1-O-Benzylglycerol HOCH2CHCH2OH HIO4 no reaction OCH2C6H5 2-O-Benzylglycerol Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 393 ALCOHOLS, DIOLS, AND THIOLS 15.40 The formation of an alkanethiol by reaction of an alkyl halide or alkyl p-toluenesulfonate with thiourea occurs with inversion of configuration in the step in which the carbon–sulfur bond is formed. Thus, the formation of (R)-2-butanethiol requires (S)-sec-butyl p-toluenesulfonate, which then reacts with thiourea by an SN2 pathway. The p-toluenesulfonate is formed from the corresponding alcohol by a reaction that does not involve any of the bonds to the stereogenic center. Therefore, begin with (S )-2-butanol. CH3CH2 H C OH CH3 CH3CH2 H C p-toluenesulfonyl chloride retention of configuration (a) H HS 2. NaOH CH2CH3 C CH3 CH3 (S )-2-Butanol 15.41 OTs 1. (H2N)2C S inversion of configuration (S )-sec-Butyl p -toluenesulfonate (R)-2-Butanethiol Cysteine contains an GSH group and is a thiol. Oxidation of thiols gives rise to disulfides. oxidize 2RSH RSSR Thiol Disulfide Biological oxidation of cysteine gives the disulfide cystine. O O 2HSCH2CHCO oxidize O OCCHCH2S NH3 NH3 Cysteine (b) SCH2CHCO NH3 Cystine Oxidation of a thiol yields a series of acids, including a sulfinic acid and a sulfonic acid. O RSH RS O 2 OH RS OH O Thiol Sulfinic acid Sulfonic acid Biological oxidation of cysteine can yield, in addition to the disulfide cystine, cysteine sulfinic acid and the sulfonic acid cysteic acid. O HSCH2CHCO NH3 Cysteine 15.42 Back Forward O oxidize HO O O oxidize SCH2CHCO HO NH3 2 SCH2CHCO O Cysteine sulfinic acid (C3H7NO4S) O NH3 Cysteic acid (C3H7NO5S) The ratio of carbon to hydrogen in the molecular formula is CnH2n 2 (C8H18O2), and so the compound has no double bonds or rings. The compound cannot be a vicinal diol, because it does not react with periodic acid. The NMR spectrum is rather simple as all peaks are singlets. The 12-proton singlet at 1.2 ppm must correspond to four equivalent methyl groups and the four-proton singlet at 1.6 ppm to two equivalent methylene groups. No nonequivalent protons can be vicinal, because no splitting is observed. The two-proton singlet at 2.0 ppm is due to the hydroxyl protons of the diol. Main Menu TOC Study Guide TOC Student OLC MHHE Website 394 ALCOHOLS, DIOLS, AND THIOLS The compound is 2,5-dimethyl-2,5-hexanediol. CH3 CH3 CH3CCH2CH2CCH3 OH 15.43 OH The molecular formula of compound A (C8H10O) corresponds to an index of hydrogen deficiency of 4. The 4 hydrogen signal at 7.2 ppm in the 1H NMR spectrum suggests these unsaturations are due to a disubstituted benzene ring. That the ring is para-substituted is supported by the symmetry of the signal; it is a pair of doublets, not a quartet. The broad signal (1H) at 2.1 ppm undergoes rapid exchange with D2O, indicating it is the proton of the hydroxyl group of an alcohol. As the remaining signals are singlets, with areas of 2H and 3H, respectively, compound A can be identified as 4-methylbenzyl alcohol. 2.4 ppm 4.7 ppm H3C CH2OH 2.1 ppm 7.2 ppm 15.44 (a) This compound has only two different types of carbons. One type of carbon comes at low field and is most likely a carbon bonded to oxygen and three other equivalent carbons. The spectrum leads to the conclusion that this compound is tert-butyl alcohol. CH3 H3C C CH3 31.2 ppm (b) OH 68.9 ppm Four different types of carbons occur in this compound. The only C4H10O isomers that have four nonequivalent carbons are CH3CH2CH2CH2OH, CH3CHCH2CH3 , and CH3OCH2CH2CH3. OH The lowest field signal, the one at 69.2 ppm from the carbon that bears the oxygen substituent, is a methine (CH). The compound is therefore 2-butanol. CH3CHCH2CH3 OH (c) This compound has two equivalent CH3 groups, as indicated by the signal at 18.9 ppm. Its lowest field carbon is a CH2, and so the group @CH2O must be present. The compound is 2methyl-1-propanol. 30.8 ppm H3C 18.9 ppm 15.45 CH CH3 CH2OH 69.4 ppm The compound has only three carbons, none of which is a CH3 group. Two of the carbon signals arise from CH2 groups; the other corresponds to a CH group. The only structure consistent with the observed data is that of 3-chloro-1,2-propanediol. HOCH2 CH CH2Cl OH Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 395 ALCOHOLS, DIOLS, AND THIOLS The structure HOCH2CHCH2OH cannot be correct. It would exhibit only two peaks in its 13C NMR Cl spectrum, because the two terminal carbons are equivalent to each other. 15.46 The observation of a peak at m/z 31 in the mass spectrum of the compound suggests the presence of a primary alcohol. This fragment is most likely H2C OH . On the basis of this fact and the appearance of four different carbons in the 13C NMR spectrum, the compound is 2-ethyl-1-butanol. 23 ppm 44 ppm CH3CH2 CH 11 ppm CH2OH CH3CH2 15.47–15.49 65 ppm Solutions to molecular modeling exercises are not provided in this Study Guide and Solutions Manual. You should use Learning By Modeling for these exercises. SELF-TEST PART A A-1. For each of the following reactions give the structure of the missing reactant or reagent. H OH (a) ? 1. LiAlH4 2. H2O OH (b) ? 1. diethyl ether 2CH3CH2MgBr C6H5C(CH2CH3)2 2. H3O CH3 (c) C6H5CH2C CH3CH2OH CH3 ? CH2 C6H5CH2CHCH2OH CH3 OH CH3 ? (d ) OH (e) A-2. C6H5CH2Br 1. ? 2. NaOH C6H5CH2SH For the following reactions of 2-phenylethanol, C6H5CH2CH2OH, give the correct reagent or product(s) omitted from the equation. PCC CH2Cl2 (a) (b) Main Menu C6H5CH2CH2OH (2 mol) (d ) Forward C6H5CH2CH2OH (c) Back C6H5CH2CH2OH C6H5CH2CH2OH TOC ? ? ? CH3CO2CH2CH2 H heat H2O ? C6H5CH2CO2H Study Guide TOC Student OLC MHHE Website 396 ALCOHOLS, DIOLS, AND THIOLS A-3. Write the structure of the major organic product formed in the reaction of 2-propanol with each of the following reagents: (a) Sodium amide (NaNH2) (b) Potassium dichromate (K2Cr2O7) in aqueous sulfuric acid, heat (c) PDC in dichloromethane O (d ) Acetic acid (CH3COH) in the presence of dissolved hydrogen chloride (e) H3C SO2Cl in the presence of pyridine O ( f) CCl in the presence of pyridine CH3CH2 OO ( g) CH3COCCH3 in the presence of pyridine A-4. Outline two synthetic schemes for the preparation of 3-methyl-1-butanol using different Grignard reagents. A-5. Give the structure of the reactant, reagent, or product omitted from each of the following. Show stereochemistry where important. OH H OH CH3 (a) (b) HIO4 ? H heat ? (a diol) O (c) OsO4, (CH3)3COOH ? (CH3)3COH, HO CH3 2,3-butanediol (chiral diastereomer) A-6. Give the reagents necessary to carry out each of the following transformations: (a) Conversion of benzyl alcohol (C6H5CH2OH) to benzaldehyde (C6H5CH O) (b) Conversion of benzyl alcohol to benzoic acid (C6H5CO2H) (c) Conversion of H2C CHCH2CH2CO2H to H2C CHCH2CH2CH2OH (d ) Conversion of cyclohexene to cis-1,2-cyclohexanediol A-7. Provide structures for compounds A to C in the following reaction scheme: A(C5H12O2) K2Cr2O7 H , H2 O B(C5H8O3) CH3OH, H C(C6H10O3) 1. LiAlH4 2. H2O H , heat A H3C Back Forward Main Menu CH3OH O TOC Study Guide TOC Student OLC MHHE Website 397 ALCOHOLS, DIOLS, AND THIOLS A-8. Using any necessary organic or inorganic reagents, outline a scheme for each of the following conversions. O (a) (CH3)2C CHCH3 ? (CH3)2CHCCH3 O O (b) (c) ? CH C6H5CH3 ? CCH2CH3 C6H5CH2CH2CO2CH2CH3 PART B B-1. Ethanethiol (CH3CH2SH) is a gas at room temperature, but ethanol is a liquid. The reason for this is (a) The C @ S @ H bonds in ethanethiol are linear. (b) The C @ O @ H bonds in ethanol are linear. (c) Ethanol has a lower molecular weight. (d ) Ethanethiol has a higher boiling point. (e) Ethanethiol is less polar. B-2. Which of the following would yield a secondary alcohol after the indicated reaction, followed by hydrolysis if necessary? (a) LiAlH4 a ketone (b) CH3CH2MgBr an aldehyde (c) 2-Butene aqueous H2SO4 (d ) All of these B-3. What is the major product of the following reaction? O NaBH4 CH3OH ? CO2H OH OH (a) (c) CH2OH CO2H OH O (b) (d ) CH2OH B-4. Back Forward Main Menu CO2CH3 Which of the esters shown, after reduction with LiAlH4 and aqueous workup, will yield two molecules of only a single alcohol? (a) CH3CH2CO2CH2CH3 (b) C6H5CO2C6H5 (c) C6H5CO2CH2C6H5 (d ) None of these TOC Study Guide TOC Student OLC MHHE Website 398 ALCOHOLS, DIOLS, AND THIOLS B-5. For the following reaction, select the statement that best describes the situation. RCH2OH (a) (b) (c) (d ) B-6. PCC [C5H5NH ClCrO3 ] The alcohol is oxidized to an acid, and the Cr(VI) is reduced. The alcohol is oxidized to an aldehyde, and the Cr(VI) is reduced. The alcohol is reduced to an aldehyde, and the Cr(III) is oxidized. The alcohol is oxidized to a ketone, and the Cr(VI) is reduced. What is the product from the following esterification? C6H5CH2CO2H 18 18 18 C6H5CH2C B-7. 18 OCH2CH3 ? O 18 C6H5CH2C (c) O (b) H heat OH O C6H5CH2COCH2CH3 (a) 18 CH3CH2 OCH2CH3 O CH3CH2COCH2C6H5 (d ) The following substance acts as a coenzyme in which of the following biological reactions? O CNH2 (R adenine dinucleotide) N R (a) (b) Alcohol oxidation Ketone reduction (c) Aldehyde reduction (d ) None of these B-8. Which of the following alcohols gives the best yield of dialkyl ether on being heated with a trace of sulfuric acid? (a) 1-Pentanol (c) Cyclopentanol (b) 2-Pentanol (d ) 2-Methyl-2-butanol B-9. What is the major organic product of the following sequence of reactions? O PBr3 (CH3)2CHCH2OH H2 C Mg CH2 H3 O ? OH (CH3)CHCHCH2CH3 (a) (c) (CH3)2CHCH2CH2OH OH (CH3)2CHCH2CHCH3 (b) (d ) (CH3)2CHCH2CH2CH2OH B-10. What is the product of the following reaction? H3C CH3 C H C H H OsO4 (cat), (CH3)3COOH (CH3)3COH, HO CH3 OH H H OH HO CH3 1 Back Forward Main Menu TOC Study Guide TOC CH3 OH H HO CH3 H H OH CH3 CH3 2 3 Student OLC MHHE Website 399 ALCOHOLS, DIOLS, AND THIOLS (a) (b) (c) Only 1 Only 2 Only 3 (d ) (e) A 1:1 mixture of 2 and 3. A 1:1:1 mixture of 1, 2, and 3. B-11. Which reaction is the best method for preparing (R)-2-butanol? O (a) (b) H3C H C 1. LiAlH4, diethyl ether CH3CH2CCH3 2. H2O O OCCH3 1. LiAlH4, diethyl ether 2. H2O CH3CH2 O (c) CH3CH2CH 1. CH3MgBr, diethyl ether 2. H3O O 1. CH3CH2Li, diethyl ether (d ) CH3CH (e) None of these would be effective. 2. H3O B-12. An organic compound B is formed by the reaction of ethylmagnesium iodide (CH3CH2MgI) with a substance A, followed by treatment with dilute aqueous acid. Compound B does not react with PCC or PDC in dichloromethane. Which of the following is a possible candidate for A? O O (a) CH3CH (d ) CH3CH2CCH3 (b) H2C (e) None of these O O (c) H2C CH2 B-13. Which alcohol of molecular formula C5H12O has the fewest signals in its spectrum? (a) 1-Pentanol (d ) 3-Methyl-2-butanol (b) 2-Pentanol (e) 2,2-Dimethyl-1-propanol (c) 2-Methyl-2-butanol 13 C NMR B-14. Which of the following reagents would carry out the following transformation? (D the mass-2 isotope of hydrogen) O CCH3 2 H, OH ? CCH3 D (a) (b) (c) (d ) (e) Back Forward Main Menu NaBD4 in CH3OH NaBD4 in CH3OD LiAlH4, then D2O LiAlD4, then D2O NaBH4 in CH3OD TOC Study Guide TOC Student OLC MHHE Website 400 ALCOHOLS, DIOLS, AND THIOLS B-15. Which sequence of steps describes the best synthesis of 2-methyl-3-pentanone? O 2-Methyl-3-pentanone (a) (b) (c) (d ) Back Forward 1. 2. 3. 1. 2. 3. 1. 2. 3. 4. 1. 2. 3. 4. Main Menu 1-Propanol (CH3)2CHMgBr, diethyl ether H3O PDC, CH2Cl2 1-Propanol Na2Cr2O7, H2SO4, H2O, heat SOCl2 (CH3)2CHCl, AlCl3 1-Propanol PCC, CH2Cl2 (CH3)2CHLi, diethyl ether H3O Na2Cr2O7, H2SO4, H2O, heat 2-Propanol Na2Cr2O7, H2SO4, H2O, heat CH3CH2CH2Li, diethyl ether H3O PCC, CH2Cl2 TOC Study Guide TOC Student OLC MHHE Website ...
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This note was uploaded on 02/16/2010 for the course CHEM CHEM231 taught by Professor Dixon during the Spring '09 term at Maryland.

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