CH 332 (Winter 2014) - Unit 4 Lecture Notes (Alcohols, Ethers and Epoxides)

Chemistry 332 Lecture Notes Unit 4 Alcohols, ethers and epoxides Introduction These lecture notes examine a variety of alcohol, ether and epoxide reactions. Overview Study Bruice 6th sections Bruice 7th sections 1 Nomenclature of alcohols and ethers 2.5, 2.6 3.5, 3.6 2 Carbocation rearrangements 4.7 (from CH 331) 6.7 (from CH 331) 3 Conversion of alcohols to alkyl halides (Route 1) 10.1 11.1 4 Conversion of alcohols to alkyl halides (Route 2) 10.2 11.2 5 Conversion of alcohols to sulfonate esters 10.3 11.3 6 Dehydration of alcohols 10.4 11.4 7 Redox reactions in organic chemistry 8 Oxidation of alcohols 10.5 11.5 9 Substitution reactions of ethers 10.6 11.6 10 Substitution reactions of epoxides (acidic conditions) 10.7 11.7 11 Substitution reactions of epoxides (neutral or basic conditions) 10.7 11.7 12 Crown ethers 10.10 11.7 13 Thiols and sulfides 10.11 11.11 Unit 4 lecture notes Page 2 of 34 Comprehensive list of learning objectives (Learning objectives form the basis for quiz and exam questions) So that you may assess your progress through the material of these lecture notes I provide the following “checklist” of learning objectives. As we move through the various Studies of these lecture notes we’ll see a re-listing of the corresponding learning objectives. At the conclusion of these lecture notes one should be able to,  give the IUPAC names of alcohols and ethers  predict whether or not a proposed carbocation rearrangement will occur (if it will you should be able to give the ensuing carbocation; if it will not you should be able to explain why)  give the mechanism (using curved arrow notation) of carbocation rearrangement  give an example of, or identify, a 1,2-hydride shift  give an example of, or identify, a 1,2-alkyl shift  invoke carbocation rearrangements when warranted  give the organic product(s) that arise from the reaction* between an alcohol and HCl, HBr or HI  predict the distribution of organic product(s) that arise from the reaction* between an alcohol and HCl, HBr or HI  explain the distribution of organic product(s) that arise from the reaction* between an alcohol and HCl, HBr or HI  give the mechanism (using curved arrow notation) for the reaction* between an alcohol and HCl, HBr or HI  give the organic product(s) that arise from the reaction** between an alcohol and PBr3, PCl3 or PI3  predict the distribution of organic product(s) that arise from the reaction** between an alcohol and PBr3, PCl3 or PI3  explain the distribution of organic product(s) that arise from the reaction** between an alcohol and PBr3, PCl3 or PI3  give the mechanism (using curved arrow notation) for the reaction** between an alcohol and PBr3, PCl3 or PI3  state the advantages of Route 2 over Route 1 as a method for the conversion of alcohols to alkyl halides  give the organic product(s) that arise from the reaction** between an alcohol and a sulfonyl chloride  predict the distribution of organic product(s) that arise from the reaction** between an alcohol and a sulfonyl chloride  explain the distribution of organic product(s) that arise from the reaction** between an alcohol and a sulfonyl chloride  give the mechanism (using curved arrow notation) for the reaction** between an alcohol and a sulfonyl chloride a) state that the dehydration of a primary alcohol proceeds via the E2 pathway b) state that the dehydration* of a secondary alcohol proceeds via the E1 pathway c) state that the dehydration* of a tertiary alcohol proceeds via the E1 pathway d) give the organic product(s) that arise from the dehydration* of an alcohol e) explain why acid (either sulfuric acid or phosphoric acid) is required f) give the reaction conditions one would employ to effect the complete dehydration of an alcohol g) predict the distribution of organic product(s) that arise from the acid-catalyzed dehydration* of an alcohol h) explain the distribution of organic product(s) that arise from the dehydration* of an alcohol i) give the mechanism (using curved arrow notation) for the dehydration* of an alcohol j) recognize whether an organic compound has been oxidized, reduced or neither, in a given reaction a) state that the treatment of methanol with aqueous chromic acid yields formic acid b) state that the treatment of a primary alcohol with aqueous chromic acid yields a carboxylic acid c) state that the treatment of a secondary alcohol with aqueous chromic acid yields a ketone d) state that the treatment of methanol with PCC in anhydrous dichloromethane (CH2Cl2) yields formaldehyde Unit 4 lecture notes Page 3 of 34 e) state that the treatment of a primary alcohol with PCC in anhydrous dichloromethane (CH2Cl2) yields an aldehyde f) state that the treatment of a secondary alcohol with PCC in anhydrous dichloromethane (CH2Cl2) yields a ketone g) give the various combinations of reagents that give aqueous chromic acid (aq H2CrO4) h) predict the organic product(s) that arise from the reaction between an alcohol and chromic acid i) predict the organic product(s) that arise from the reaction between an alcohol and PCC in anhydrous dichloromethane a) give the organic product(s) that arise from the reaction* between an ether and HCl, HBr or HI b) predict the distribution of organic product(s) that arise from the reaction* between an ether and HCl, HBr or HI c) explain the distribution of organic product(s) that arise from the reaction* between an ether and HCl, HBr or HI d) give the mechanism (using curved arrow notation) for the reaction* between an ether and HCl, HBr or HI a) give the organic product(s) that arise from the substitution reactions of epoxides under acidic conditions b) predict the distribution of organic product(s) that arise from the substitution reactions of epoxides under acidic conditions c) explain the distribution of organic product(s) that arise from the substitution reactions of epoxides under acidic conditions d) give the mechanism (using curved arrow notation) for the substitution reactions of epoxides under acidic conditions a) give the organic product(s) that arise from the substitution reactions of epoxides under neutral or basic conditions b) predict the distribution of organic product(s) that arise from the substitution reactions of epoxides under neutral or basic conditions c) explain the distribution of organic product(s) that arise from the substitution reactions of epoxides under neutral or basic conditions d) give the mechanism (using curved arrow notation) for the substitution reactions of epoxides under neutral or basic conditions * carbocations involved, therefore one or more carbocation rearrangements may occur (following the rules in Study 2) **in the presence of pyridine Unit 4 lecture notes Page 4 of 34 Study 1 Independent study of nomenclature of alcohols and ethers Introduction This independent Study examines the IUPAC system for naming alcohols and ethers Bruice 6th section(s) 2.5, 2.6 Bruice 7th section(s) 3.5, 3.6 Learning objective(s) At the conclusion of this independent Study one should be able to give the IUPAC names of alcohols and ethers. Study 2 Carbocation rearrangements Introduction This Study reviews carbocation rearrangements are discussed in Chemistry 331. Carbocation rearrangements occur in certain alcohol reactions. Bruice 6th section(s) 4.7 Bruice 7th section(s) 6.7 Learning objective(s) At the conclusion of this Study one should be able to, a) predict whether or not a proposed carbocation rearrangement will occur (if it will you should be able to give the ensuing carbocation; if it will not you should be able to explain why) b) give the mechanism (using curved arrow notation) of carbocation rearrangement c) give an example of, or identify, a 1,2-hydride shift d) give an example of, or identify, a 1,2-alkyl shift e) invoke carbocation rearrangements when warranted Whenever a carbocation is involved in an organic reaction, we need to consider the possibility that one or more carbocation rearrangements may occur. Rules governing carbocation rearrangements -as a general rule a 1,2-shift of hydride will occur if it results in a more stable carbocation -as a general rule a 1,2-shift of an alkyl group (e.g. methyl, ethyl, propyl, or any other type of alkyl group for that matter) will occur if it results in a more stable carbocation Unit 4 lecture notes Page 5 of 34 Rule 1 A carbocation rearrangement that leads to a more stable carbocation will occur -i.e. primary (1°) to secondary (2°); primary (1°) to tertiary (3°); secondary (2°) to tertiary (3°) e.g. H CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H CH3 a secondary (2o) carbocation CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H CH3 a tertiary (3o) carbocation H 1,2-hydride shift ALLOWED CH3 CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H CH3 a secondary (2o) carbocation CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H CH3 a tertiary (3o) carbocation CH3 1,2-metthyl shift ALLOWED CH3 CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H CH3 a secondary (2o) carbocation CC CH3 H C CH2CH2CH2CH3 H H CH3 a tertiary (3o) carbocation CH2CH2CH2CH3 1,2-butyl shift ALLOWED Rule 2 A carbocation rearrangement that leads to a less stable carbocation will not occur -i.e. 3° to 1°; 3° to 2°; 2° to 1° e.g. 1,2-hydride shift H CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H H a secondary (2o) carbocation H CC CH2CH2CH2CH3 H C CH2CH2CH2CH3H H a primary (1o) carbocation H N O T A L L O W E D Unit 4 lecture notes Page 6 of 34 Rule 3 A carbocation rearrangement that leads to a different carbocation of the same class will not occur -i.e. 1° to 1°; 2° to 2°; 3° to 3° e.g. H CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H CH3 a secondary (2o) carbocation CC CH2CH2CH2CH3 CH2CH2CH2CH3 C H H CH3 a secondary (2o) carbocation H H 1,2-butyl shift (a type of 1,2-alkyl shift) N O T A L L O W E D N O T A L L O W E D H CC CH2CH2CH2CH3 H C CH2CH2CH2CH3 H H CH3 a secondary (2o) carbocation CC CH2CH2CH2CH3 H C CH2CH2CH2CH3H CH3 a secondary (2o) carbocation H 1,2-hydride shift H Rule 4 Rules 2 and 3 are overridden whenever the carbocation rearrangement leads to a reduction in ring strain e.g. a secondary (2o) carbocation H CH3 H 1,2-alkyl shift (Cd migrates from Ca to Ce) a b c d e a b c d e H H CH3 ALLOWED a secondary (2o) carbocation 1,2-hydride shift ALLOWED a b c d e H CH3 H highly strained four-membered ring much less strained five-membered ring Unit 4 lecture notes Page 7 of 34 Study 3 Conversion of alcohols to alkyl halides (Route 1) Introduction This Study examines the conversion of an alcohol to an alkyl halide through treatment with HCl, HBr or HI. We will consider a number of important questions. How do these reactions occur? What products are formed? Why are some products the major products while others are the minor products? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? H C C X HX H C C OH Bruice 6th section(s) 10.1 Bruice 7th section(s) 11.1 Learning objective(s) At the conclusion of this Study one should be able to, a) give the organic product(s) that arise from the reaction* between an alcohol and HCl, HBr or HI b) predict the distribution of organic product(s) that arise from the reaction* between an alcohol and HCl, HBr or HI c) explain the distribution of organic product(s) that arise from the reaction* between an alcohol and HCl, HBr or HI d) give the mechanism (using curved arrow notation) for the reaction* between an alcohol and HCl, HBr or HI * carbocations involved, therefore one or more carbocation rearrangements may occur (following the rules in Study 2) Unit 4 lecture notes Page 8 of 34 Overview of Route 1 HCl, HBr, HI R OH R O H H SN2 pathway, if alcohol is . carbocation invoke appropriate rearrangements R X hydroxide is a poor leaving group water is a good leaving group SN1 pathway, if alcohol is . R X X Relevant alcohols CH3OH, methanol RCH2OH, a primary (1 0) alcohol R2CHOH, a secondary (2 0) alcohol R3COH, a tertiary (3 0) alcohol Problem solving strategy 1. Identify the type of alcohol 2. Select pathway (SN1 or SN2) 3. Use reaction mechanism to determine product(s) Let’s take a look at a few worked examples HI HO HBr OH Unit 4 lecture notes Page 9 of 34 OH HCl H Unit 4 lecture notes Page 10 of 34 HBr C OH CH3 CH3 CH3OH HBr CH3Br Mg in dry diethyl ether CH3MgBr O 1 in diethyl ether 2. H3O + CH3CH2CH2OH no direct path MAKING CONNECTIONS Unit 4 lecture notes Page 11 of 34 Study 4 Conversion of alcohols to alkyl halides (Route 2) Introduction This Study examines the conversion of an alcohol to an alkyl halide through treatment with PBr3, PCl3 or PI3 (in the presence of pyridine). We will consider a number of important questions. How do these reactions occur? What products are formed? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? H C C XH C C OH PBr3, PCl3 or PI3 and pyridine (as solvent and as proton scavenger) Bruice 6th section(s) 10.2 Bruice 7th section(s) 11.2 Learning objective(s) At the conclusion of this Study one should be able to, a) predict the distribution of organic product(s) that arise from the reaction* between an alcohol and PBr3, PCl3 or PI3 b) explain the distribution of organic product(s) that arise from the reaction* between an alcohol and PBr3, PCl3 or PI3 c) give the mechanism (using curved arrow notation) for the reaction* between an alcohol and PBr3, PCl3 or PI3 d) state the advantages of Route 2 over Route 1 as a method for the conversion of alcohols to alkyl halides *in the presence of pyridine Unit 4 lecture notes Page 12 of 34 Overview of Route 2 R OH R O Reaction occurs if alcohol is . R X hydroxide is a poor leaving group a halophosphite group which is a good leaving group X Relevant alcohols CH3OH, methanol RCH2OH, a primary (1 0) alcohol R2CHOH, a secondary (2 0) alcohol R3COH, a tertiary (3 0) alcohol Problem solving strategy 1. Identify the type of alcohol 2. Decide if alcohol will react 3. Use reaction mechanism to determine product a phosphorus trihalidePX3 P X X X Reaction does not occur if alcohol is . in pyridine (solvent and proton scavenger) Let’s take a look at a few worked examples PCl3, pyridine C OH CH3 CH3 OH PBr3, pyridine H PCl3, pyridine OH Unit 4 lecture notes Page 13 of 34 Li in dry hexane no direct path OH PBr3, pyridine Br Li O 1 in diethyl ether 2. H3O + OH MAKING CONNECTIONS Study 5 Conversion of alcohols to alkyl sulfonate esters Introduction This Study examines the conversion of an alcohol to an alkyl sulfonate ester through treatment with a sulfonyl chloride (in the presence of pyridine). We will consider a number of important questions. How do these reactions occur? What products are formed? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? H C C OSO2R 'H C C OH pyridine (as solvent and as proton scavenger) Cl S O O R1 Bruice 6th section(s) 10.3 Bruice 7th section(s) 11.3 Learning objective(s) At the conclusion of this Study one should be able to, a) give the organic product(s) that arise from the reaction* between an alcohol and a sulfonyl chloride b) predict the distribution of organic product(s) that arise from the reaction* between an alcohol and a sulfonyl chloride c) explain the distribution of organic product(s) that arise from the reaction* between an alcohol and a sulfonyl chloride d) give the mechanism (using curved arrow notation) for the reaction* between an alcohol and a sulfonyl chloride *in the presence of pyridine Unit 4 lecture notes Page 14 of 34 Overview of alkyl sulfonate ester formation R OH hydroxide is a poor leaving group excellent leaving group (100 times better than chloride ion!!) Types of alcohols CH3OH, methanol RCH2OH, a primary (1 0) alcohol R2CHOH, a secondary (2 0) alcohol R3COH, a tertiary (3 0) alcohol Problem solving strategy 1. Identify the type of alcohol 2. Decide if alcohol will react 3. Use reaction mechanism to determine product in pyridine (solvent and proton scavenger) R O S O O R1 an alkyl sulfonate ester Cl S O O R1 a sulfonyl chloride Typical sulfonyl chlorides (R1SO2Cl) CH3 S O O Cl para-toluenesulfonyl chloride (aka tosyl chloride) (aka TsCl) CH3 S O O Cl methanesulfonyl chloride (aka mesyl chloride) (MsCl) CF3 S O O Cl trifluoromethanesulfonyl chloride (aka triflyl chloride) (aka TfCl) Typical sulfonate esters (R1SO2OR) CH3 S O O OR a para-toluenesulfonate ester (a tosylate) (aka ROTs) CH3 S O O OR a methanesulfonate ester (a mesylate) (aka ROMs) CF3 S O O OR a trifluoromethanesulfonate ester (a triflate) (aka ROTf) Unit 4 lecture notes Page 15 of 34 Let’s take a look at a few worked examples OH MsCl, pyridine TsCl (1 mole), pyridine OH OH 1 mole Alkyl sulfonate esters in synthesis MsCl, in pyridine CH3CH2CN no direct path MAKING CONNECTIONS NaCN, DMSO, heat from CH 331 CH3CH2OH CH3CH2OMs TsCl, in pyridine CH3CH2SCH3 no direct path MAKING CONNECTIONS NaSCH3, DMSO, heat from CH 331 CH3CH2OH CH3CH2OTs Unit 4 lecture notes Page 16 of 34 Study 6 Dehydration of alcohols Introduction This Study examines the acid-catalyzed dehydration of alcohols. We will consider a number of important questions. How do these reactions occur? What products are formed? Why are some products the major products while others are the minor products? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? H2SO4 (or H3PO4) heat H C C OH Bruice 6th section(s) 10.4 Bruice 7th section(s) 11.4 Learning objective(s) At the conclusion of this Study one should be able to, a) state that the dehydration of a primary alcohol proceeds via the E2 pathway b) state that the dehydration* of a secondary alcohol proceeds via the E1 pathway c) state that the dehydration* of a tertiary alcohol proceeds via the E1 pathway d) give the organic product(s) that arise from the dehydration* of an alcohol e) explain why acid (either sulfuric acid or phosphoric acid) is required f) give the reaction conditions one would employ to effect the complete dehydration of an alcohol g) predict the distribution of organic product(s) that arise from the acid-catalyzed dehydration* of an alcohol h) explain the distribution of organic product(s) that arise from the dehydration* of an alcohol i) give the mechanism (using curved arrow notation) for the dehydration* of an alcohol * carbocations involved, therefore one or more carbocation rearrangements may occur (following the rules in Study 2) Unit 4 lecture notes Page 17 of 34 Overview of alcohol dehydration R OH R O H H E2 pathway, if alcohol is . carbocation invoke appropriate rearrangements hydroxide is a poor leaving group water is a good leaving group E1 pathway, if alcohol is . Relevant alcohols CH3OH, methanol RCH2OH, a primary (1 0) alcohol R2CHOH, a secondary (2 0) alcohol R3COH, a tertiary (3 0) alcohol Problem solving strategy 1. Identify the type of alcohol 2. Select pathway (E1 or E2) 3. Use reaction mechanism to determine product(s) H2SO4 (or H3PO4) OSO3H Conditions employed to effect the complete dehydration of an alcohol Unit 4 lecture notes Page 18 of 34 Predicting the distribution of alkene products -relative stabilities of a few alkenes (data from: J.D. Rockenfeller, F.D. Rossini Journal of Physical Chemistry, 1961, p267) e.g. e.g. Hhydrogenation = -28.0 kcal/mole energy Hhydrogenation = -26.9 kcal/mole Hhydrogenation = -28.0 kcal/mole energy Hhydrogenation = -26.5 kcal/mole R R R R > R R R H > R R H H > R H R H H R R H > H H R H > H H H H tetra- substituted alkenes tri- substituted alkenes di- substituted alkenes di- substituted alkenes mono- substituted alkenes ethylene most stable alkene least stable alkene Unit 4 lecture notes Page 19 of 34 Let’s take a look at a few worked examples OH H2SO4, heat H2SO4, heat OH Unit 4 lecture notes Page 20 of 34 H2SO4, heat OH Unit 4 lecture notes Page 21 of 34 Study 7 Redox reactions in organic chemistry Introduction This unit examines the method for determining whether an organic compound has been oxidized, reduced or neither, in a given reaction Bruice section(s) N/A Learning objective(s) At the conclusion of this Study one should be able to recognize whether an organic compound has been oxidized, reduced or neither, in a given reaction How does one decide whether an organic compound has been reduced or oxidized? Step 1 Begin by calculating oxidation levels for the reactant and product Oxidation level = # CA bonds - # CH bonds - # CB bonds -where A represents an atom that is more electronegative than carbon; where B represents an atom that is less electronegative than carbon Step 2 If the net change in oxidation levels is positive then the reactant has been oxidized If the net change in oxidation levels is negative then the reactant has been reduced If there is no net change in oxidation levels then the reactant has neither been reduced nor oxidized Let’s look at a few examples Oxidation level of Net change in oxidation level Reactant has been reactant product a) O O O Oxidized Reduced Neither oxidized nor reduced b) F Oxidized Reduced Neither oxidized nor reduced c) Oxidized Reduced Neither oxidized nor reduced Unit 4 lecture notes Page 22 of 34 Study 8 Oxidation of alcohols Introduction This Study examines the oxidations of alcohols. We will consider a number of important questions. How do these reactions occur? What products are formed? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? R CH2OH O CR H O CR OH R CH O CR R O CR R R OH a primary alcohol a secondary alcohol an aldehyde a carboxylic acid a ketone a ketone Bruice 6th section(s) 10.5 Bruice 7th section(s) 11.5 Learning objective(s) At the conclusion of this Study one should be able to, a) state that the treatment of methanol with aqueous chromic acid yields formic acid b) state that the treatment of a primary alcohol with aqueous chromic acid yields a carboxylic acid c) state that the treatment of a secondary alcohol with aqueous chromic acid yields a ketone d) state that the treatment of methanol with PCC in anhydrous dichloromethane (CH2Cl2) yields formaldehyde e) state that the treatment of a primary alcohol with PCC in anhydrous dichloromethane (CH2Cl2) yields an aldehyde f) state that the treatment of a secondary alcohol with PCC in anhydrous dichloromethane (CH2Cl2) yields a ketone g) give the various combinations of reagents that give aqueous chromic acid (aq H2CrO4) h) predict the organic product(s) that arise from the reaction between an alcohol and chromic acid i) predict the organic product(s) that arise from the reaction between an alcohol and PCC in anhydrous dichloromethane Unit 4 lecture notes Page 23 of 34 How to prepare aqueous chromic acid  Recipe #1 H2O Na2Cr2O7 + H2SO4 H2CrO4 sodium dichromate sulfuric acid chromic acid  Recipe #2 H2O CrO3 + H2SO4 H2CrO4 chromium trioxide sulfuric acid chromic acid Let’s take a look at a few worked examples aqueous H2CrO4 OH aqueous H2CrO4OH Unit 4 lecture notes Page 24 of 34 OH aqueous H2CrO4 Unit 4 lecture notes Page 25 of 34 Cut off for the Midterm Exam Study 9 Substitution reactions of ethers Introduction This Study examines the substitution reactions of ethers. We will consider a number of important questions. How do these reactions occur? What products are formed? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? 2 HX R O R' R X R' X Bruice 6th section(s) 10.6 Bruice 7th section(s) 11.6 Learning objective(s) At the conclusion of this Study one should be able to, a) give the organic product(s) that arise from the reaction* between an ether and HCl, HBr or HI b) predict the distribution of organic product(s) that arise from the reaction* between an ether and HCl, HBr or HI c) explain the distribution of organic product(s) that arise from the reaction* between an ether and HCl, HBr or HI d) give the mechanism (using curved arrow notation) for the reaction* between an ether and HCl, HBr or HI * carbocations may be involved, therefore one or more carbocation rearrangements may occur (following the rules in Study 2) Unit 4 lecture notes Page 26 of 34 An overview 2 HX (HCl, HBr or HI) R OR R O H R SN2 pathway, if the R group is . carbocation invoke appropriate rearrangements R X alkoxides are poor leaving groups alcohols are good leaving groupsX SN1 pathway, if the R group is . R X R X R X Unit 4 lecture notes Page 27 of 34 Let’s take a look at a few examples O HI HBr O Unit 4 lecture notes Page 28 of 34 Study 10 Substitution reactions of epoxides under acidic conditions Introduction This Study examines the substitution reactions of epoxides under acidic conditions. We will consider a number of important questions. How do these reactions occur? What products are formed? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? Bruice 6th section(s) 10.7 Bruice 7th section(s) 11.7 Learning objective(s) At the conclusion of this Study one should be able to, a) give the organic product(s) that arise from the substitution reactions of epoxides under acidic conditions b) predict the distribution of organic product(s) that arise from the substitution reactions of epoxides under acidic conditions c) explain the distribution of organic product(s) that arise from the substitution reactions of epoxides under acidic conditions d) give the mechanism (using curved arrow notation) for the substitution reactions of epoxides under acidic conditions Let’s take a look at a few examples Unit 4 lecture notes Page 29 of 34 Unit 4 lecture notes Page 30 of 34 Study 11 Substitution reactions of epoxides under neutral or basic conditions Introduction This Study examines the substitution reactions of epoxides under neutral or basic conditions. We will consider a number of important questions. How do these reactions occur? What products are formed? Is there a discernible pattern to this type of reaction and can it be used as a reliable predictor for reaction outcomes? Bruice 6th section(s) 10.7 Bruice 7th section(s) 11.7 Learning objective(s) At the conclusion of this Study one should be able to, a) give the organic product(s) that arise from the substitution reactions of epoxides under neutral or basic conditions b) predict the distribution of organic product(s) that arise from the substitution reactions of epoxides under neutral or basic conditions c) explain the distribution of organic product(s) that arise from the substitution reactions of epoxides under neutral or basic conditions d) give the mechanism (using curved arrow notation) for the substitution reactions of epoxides under neutral or basic conditions Let’s take a look at a few examples i) O H H 1. NaN3 2. H3O + Na+ as counter ion N3 as nucleophile a b Ca is a secondary center and thus suited to SN2 attack Cb is a secondary center and thus suited to SN2 attack Ca and Cb are equally likely to be attacked. This leads to equal amounts of the products shown. OH H H N3 H OH N3 H formed in equal amounts (as a racemic mixture) Reaction mechanism for the formation of first product O H H a b N3 O H H N3 H3O + OH H H N3 The nucleophile attacks from the side opposite the epoxide ring (note the inversion of configuration at Ca) Na+ Na+ a b a b Unit 4 lecture notes Page 31 of 34 ii) 1. NaOCH3 2. H3O + Na+ as counter ion OCH3 as nucleophile a b Ca is a tertiary center and thus not suited to SN2 attack Cb is a primary center and thus suited to SN2 attack product arises solely from attack at Cb Reaction mechanism H3O + Na+ O a b O OCH3 CH2OCH3 O Na+ CH2OCH3 OH CH2OCH3 OH sole organic product a b a b iii) CH3Li, dry ether 2. H3O + Li+ as counter ion CH3 as nucleophile a b Ca is a secondary center and thus suited to SN2 attack Cb is a primary center and thus suited to SN2 attack Greater steric hindrance associated with attack at Ca. Therefore the major organic product arises from attack at Cb H3O + O CH2CH3 OH H H CH2OH H CH3 major organic product minor organic product Reaction mechanism for the formation of first product O H CH3 a b CH2CH3 O H Li+ Li+ CH2CH3 OH H H3O + Reaction mechanism for the formation of second product O H CH3 a b CH2O H CH3 Li+ Li+ CH2OH H CH3 a b a b a b a b Unit 4 lecture notes Page 32 of 34 Study 12 Crown ethers Introduction This Study is a brief survey of crown ethers. Bruice 6th section(s) 10.10 Bruice 7th section(s) 11.7 Learning objective(s) This Study is included for informational purposes only. You will not be tested on Study 12 Crown ethers are a class of cyclic compounds that possess an array of ether groups about a central cavity. Certain crown ethers are able to form inclusion compounds. e.g. O O O O [12]-crown-4 Li O O O O Li bound in [12]-crown-4 Li For an interesting discussion of the link between nonactin’s ability to act like a crown ether and its antibiotic behavior please see Bruice page 440. Study 13 Thiols and sulfides Introduction This Study is a brief survey of thiols and sulfides. Bruice 6th section(s) 10.11 Bruice 7th section(s) 11.11 Learning objective(s) This Study is included for informational purposes only. You will not be tested on Study 13. Thiols Thiols are also known as mercaptans Thiols are sulfur analogues of alcohols e.g. SH SH Unit 4 lecture notes Page 33 of 34 The amino acid cysteine (shown below) contains a thiol H3N CH C CH2 OH O SH Thiols (pKa ~ 10) are stronger acids than alcohols (pka ~ 15) since thiolate ions are more stable than alkoxide ions. SH S a thiol a thiolate ion NaH Na Thiolate ions are good nucleophiles S a thiolate ion CH3Br, DMSO, heat SCH3 a sulfide Sulfides Sulfides are also known as thioethers Sulfides are sulfur analogues of ethers Sulfides are good nucleophiles CH3CH2Br, DMSO, heat SCH3 a sulfide SCH3 a sulfonium salt CH2CH3 Br Unit 4 lecture notes Page 34 of 34 Although the following assigned questions are not turned in they provide an excellent opportunity for you to assess your progress through the course material. Assigned questions Correlated to Bruice 6th and Bruice 7th Bruice 6th Bruice 7th Bruice 6th Bruice 7th Bruice 6th Bruice 7th 2.18a 3.20a 10.12c 11.15a 10.33(all but g) 11.48(all but g) 2.20 3.22 10.13b 11.15b 10.38(a,b,c,d,e,f,g) 11.54(a,b,c,d,e,f,g) 10.5 11.5(a,b,c,f) 10.14 11.18 10.48 11.69 10.7 11.10 10.17 11.21 10.52 11.72 10.10 11.13 10.20 11.24 10.55 11.75 10.12(a,b) 11.14 10.21 11.25 Additional assigned questions Solutions are available on Blackboard 1. Deduce the structures of compounds A, B and C. Don’t forget to use wedge/dash notation where appropriate. OH HO NaH (1 mole), DMF Br BnBr A PCC dry CH2Cl2 B C 1 mole BnBr (1 mole), DMF, heat 2. Deduce the structures of compound D and E. Don’t forget to use wedge/dash notation where appropriate. H OCH3 HO OH OH TsCl (1 mole), pyridine NaCN, DMSO, heat (1 mole) D E 3. Deduce the structures of compounds F, G, and H. Don’t forget to use wedge/dash notation where appropriate. 1. F, dry ether 2. H3O + G PCC, dry CH2Cl2 F H Br Li, hexane O