CFQ & PP: Carbonyl Chemistry: Survey of Reactions and Mechanisms Reading Brown and Foote: Sections 15.1, 16.6 – 16.11, 16.13, 16.14 17.4 – 17.8, 18.2
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[Show More] and 18.4 – 18.12 Lecture Supplement Ca rbonyl Reaction Catalysis (page 50 of this Thinkbook) Suggested Text Exercises Brown and Foote: Chapter 15: 1, 2 Chapter 16: 4 – 11, 12 – 14, 19 – 45, 54 – 68 Chapter 17: 2 – 5, 18 – 43 Chapter 18: 2 – 12, 20 - 53 Optional Interactive Organic Chemistry CD and Workbook Supporting Concepts: Carbonyl Chemistry (p. 70) Mechanisms: Acid Anhydride Hydrolysis (p. 17) Acid-Catalyzed Formation of an Acetal (p. 18) Acid-Catalyzed Formation of a Hemiacetal (p. 19) Acid Chloride Hydrolysis (p. 19) Acid Hydrolysis of an Amide (p. 20) Base Hydrolysis of an Amide (p. 21) Base Hydrolysis of a Nitrile (p. 21) Ester Hydrolysis in Aqueous Base (p. 25) Fischer Esterification (p. 25) Formation of a Cyanohydrin (p. 26) Formation of an Imine from a Ketone (p. 26) Nylon Formation (p. 29) Reaction of an Ester with a Grignard Reagent (p. 31) Reduction of an Amide by LAH (p. 31) Reduction of an Ester by LAH (p. 32) Sodium Borohydride Reduction of a Ketone (p. 32) Wittig Reaction (p. 32) Wolff-Kishner Reduction (p. 32) Reactivity Explorer: Acid Chlorides and Anhydrides (p. 40) Amides (p. 43) Carboxylic Acids (p. 44) Esters (p. 45) Ketones and Aldehydes (p. 46)CFQ & PP: Carbonyl Chemistry: Survey of Reactions and Mechanisms 181 Concept Focus Questions 1. Shown below is the formation of cyclic glucopyranose from acyclic glucose, an example of the intramolecular formation of a hemiacetal. O OH HO HO HOHO a-D-glucopyranose OH O HO HO HOHO H D-glycose (acyclic) O HO HO HOHO OH b-D-glucopyranose H 2O H2O (a) Show the mechanism of the reaction. (b) Why is the reaction faster in the presence of acid? (c) Why is the reaction faster in the presence of base? (d) How would the reactants be different if this reaction occurred in a living cell? 2. The reaction of retinal and opsin to form rhodopsin, a key step in the chemistry of vision, is an example of imine formation. R NH2 CH3 H 3C H3C CH3 O H CH3 CH3 H 3C H3C CH3 N H CH3 R opsin (R = rest of protein) retinal H3O+ rhodopsin (a) Write a mechanism for this reaction. (b) Explain how the mechanism suggests that H3O+ need be present in only a catalytic quantity for this reaction. 3. Reaction of a carboxylic acid with a large excess of an alcohol in the presence of a strong acid (usually H2SO4) is called the Fischer esterification. Ph OH O H 2SO4 CH3OH Ph OCH3 O (a) Give two specific reasons why must the carboxylic acid carbonyl be protonated prior to nucleophilic attack. (b) The first step of the mechanism is protonation of methanol and not the carboxylic acid. Explain. (c) In the second step of the mechanism, the carboxylic acid accepts a proton on the carbonyl oxygen instead of the hydroxyl oxygen. Explain this regioselectivity. (d) Provide a complete mechanism for this Fischer esterification. (e) How strong must the acid be?182 CFQ & PP: Carbonyl Chemistry: Survey of Reactions and Mechanisms (f) Suggest a general guideline concerning the necessity of carbonyl group protonation prior to nucleophilic attack. 4. Metal hydrides can be used to reduce an aldehyde or ketone into an alcohol. Write the mechanisms of the following reactions. H3C CH3 O NaBH4 H3C CH3 CH3CH2OH OH 1. LiAlH4 2. aq. H2SO4 H 3C CH3 OH 5. Grignard reactions involve the combination of a Grignard reagent of general form RMgX with a carbonyl compound. These reactions are commonly used to make carbon-carbon bonds, as shown below. Ph Ph O 1. CH3MgBr 2. aq. H2SO4 Ph Ph HO CH3 or Ph OCH3 O 1. CH3MgBr 2. aq. H2SO4 Ph CH3 HO CH3 (a) Define "organometallic compound." (b) Why do organometallic reagents provide a source of nucleophilic carbon groups? (c) Provide the mechanisms for both reactions given above. (d) Although carbon and magnesium are both common elements in the human body, Grignard reactions do not occur in cells. Why is this so? 6. Describe how the Wittig reaction could be used to transform benzaldehyde into styrene. Include all relevant reactions and mechanisms. Concept Focus Questions Solutions 1. (a) OH O HO HO HOHO H O O HO HO HOHO H H OH2 O O HO HO HOHO H H 2O H O OH HO HO HOHO H The other diastereomer (b-D-glucopyranose) is formed by an identical mechanism. The timing of proton transfer steps in this mechanism is not crucial. The alkoxide oxygen could be protonated prior to deprotonation of the oxonium ion. Because proton transfers are common mechanism steps, this timing issue will be encountered frequently. (b) Protonation of the alkoxide (RO-) of the tetrahedral intermediate bearing the negative charge in the last mechanism step shifts the last mechanism stepCFQ & PP: Carbonyl Chemistry: Survey of Reactions and Mechanisms 183 equilibrium further to the right, thus accelerating the reaction overall. Also, protonation of the carbonyl oxygen atom increases the electrophilicity of the carbonyl group. (c) Deprotonation of the oxonium ion (R2OH+) of the tetrahedral intermediate at the end of the first step makes for a poorer leaving group. This disfavors return to the acyclic glucose, shifting the equilibrium to the right, and thus accelerating the reaction overall. Also, deprotonation converts the alcohol (a weak nucleophile) into an alkoxide (a stronger nucleophile). (d) In a living cell the proton would probably be "shuttled" by an enzyme instead of by water. A sufficiently acidic proton within the enyzme would be the acid and some lone pair within the enzyme would be the base. 2. (a) RNH2 O ret H H ret H N O H R H OH2 H ret H N OH H R H ret H N OH OH2 R H OH2 H ret H N OH2 R H ret N H R H ret N H R OH2 H ret N R + H 3O Dehydration may also occur by an E2-like pathway. H ret H2O H N OH2 R H ret N R + H3O + H2O (b) A catalyst participates in the reaction, altering the mechanism and increasing the reaction rate, and returns to its original structure at the end. Hydronium ion is a catalyst for this reaction because it is regenerated in the last step. 3. (a) Reason 1: A carboxylic acid is a poor electrophile due to significant resonance between the carbonyl and hydroxyl groups. Nucleophilic attack would result in loss of this stabilizing resonance, so resonance inhibits nucleophilic attack. Reason 2: An alcohol is a poor nucleophile due to the high electronegativity of oxygen. (b) Protonation of the carboxylic acid increases resonance whereas protonation of the alcohol does not. Therefore we might predict the carboxylic acid to be protonated in preference to the alcohol. However, for reasons that defy our simplistic predictions of basicity, the alcohol is more basic. (It is probably due to subtle inductive effects.)184 CFQ & PP: Carbonyl Chemistry: Survey of Reactions and Mechanisms (c) Protonation of the carbonyl oxygen leads to an oxonium ion that can stabilize the positive charge by resonance. No such resonance is possible when the hydroxyl oxygen is protonated. OH O H OH O H OH2 O X Resonance delocalization of positive charge. No other significant resonance contributors. (d) Ph OH O H OCH3 Ph OH OH CH3OH Ph CH3OH H OCH3 HO OH Ph OCH3 HO OH H HO3SO H + HOCH3 HO3SO + H OCH3 H H OCH3 H Ph OCH3 HO OH2 Ph OCH3 O H Ph OCH3 O H HOCH3 Ph OCH3 O + H2OCH3 Dehydration may also occur by an E2-like pathway. Ph OCH3 O OH2 Ph OCH3 O + H 2OCH3 + H2O CH3OH H Methanol is protonated before the carbonyl because methanol is a stronger base. (While this does not agree with our simplistic predictions about basicity, it is an empirical fact, and cannot be ignored.) In addition, we use methanol as the solvent (large excess) to push the equilibrium toward the ester. There is so much more methanol than carboxylic acid that is it much more likely for H2SO4 to encounter CH 3OH than PhCO2H. (e) For the reaction to proceed at a reasonable rate, the acid must be rather strong. Sulfuric and phosphoric acids are usually used. Weaker acids such as acetic acid are not sufficiently acidic to protonate the alcohol or carbonyl group to any useful extent. (f) Protonation of a carbonyl group increases its electrophilicity and hence susceptibility to nucleophilic attack. However, the carbonyl does not need to be [Show Less]