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Review from 1st Year Organic Chemistry: g y Synthesis & Reactions of Alkenes Di Discussed briefly in class: Chapter 8 (except 8.9‐ d b i fl i l Ch t 8 ( t 8 9 8.11) 8 11) Material that should be reviewed independently: Chapter 7 1 Chemistry Connections Terpenes in Natural Product Synthesis • Terpenes represent the largest class of secondary metabolites that are made up of linked isoprene units, t b lit th t d f li k d i it leading to an extensive array of complex molecular structures with a broad range of biological properties. Terpenes as Anti‐HIV Drugs • HIV is a global epidemic with over 35 million people carrying the virus world‐wide! • New anti‐retrovirals with y y better efficacy and safety are needed Thunder Duke Vine (tripterygium wilfordii) 2 Reaction of Alkenes: HX Addition Markovnikov’s Rule: In electrophilic addition reactions of M k ik ’ R l I l t hili dditi ti f alkenes, the electrophile adds to the least substituted carbon giving rise to the more stable intermediate. Example: Addition of HX Markovnikov Addition (only product) Non‐Markovnikov Addition (NOT observed) Regioselectivity: When two or more regioisomers (constitutional R i l i i Wh i i ( i i l isomers) are possible but one is preferentially formed 3 Reaction of Alkenes: Halogenation with X2 Chlorine (Cl2) and bromine (Br2) react with alkenes to give dihalide products through an anti‐addition mechanism: Br Br Br CH2Cl2 Br + H H H Br H Br bromonium ion Stereoselectivity: The preferential formation of one stereoisomer over another. Example: anti‐addition vs syn‐addition th E l ti dditi dditi 4 Reaction of Alkenes: Halohydrin formation (X2 and H2O) The bromonium ion can be ring‐opened by a variety of nucleophiles, including water: bromonium ion The concentration of water (solvent) is very high so it beats the bromide anion as a nucleophile the bromide anion as a nucleophile 5 Reaction of Alkenes: Halohydrin Regioselectivity The bromonium ion is opened by the nucleophilic water at the higher‐substituted carbon because the partial positive charge is more stabilized (hyperconjugation): more stabilized (hyperconjugation): 6 Hydration of Alkenes: Oxymercuration Oxymercuration is a two‐step reaction for the hydration of alkenes f h h d f lk that gives Markovnikov alcohol products: Partial Mechanism: Partial Mechanism: 7 Hydration of Alkenes: Hydroboration Hydroboration is also a two‐step reaction for the hydration of H d b ti i l t t ti f th h d ti f alkenes that produces syn non‐Markovnikov alcohol products: 3 3 3 2 3 Non-Markovnikov (syn-addition) 2, Partial Mechanism: CH3 BH3 H H B H H CH3 H2O2, H BH2 CH3 NaOH C H3 H OH r e m o i t n a n +e H H The reaction is regioselective The reaction is regioselective (alcohol on the least‐substituted carbon) (alcohol on the least substituted carbon) and stereoselective (syn‐addition) 8 Hydrogenation of Alkenes to Alkanes Hydrogenation involves the syn‐addition of H2 to an alkene using a catalyst (ex. Pd/C, PtO2): Partial Mechanism: Partial Mechanism: 9 Dihydroxylation of Alkenes OsO4 allows for the syn‐selective addition of two hydroxyl groups: Partial Mechanism: Partial Mechanism: Due to the toxicity of OsO4, it is sometimes used in a catalytic amount with a stoichiometric amount of t l ti t ith t i hi ti t f N‐methylmorpholine N‐oxide (NMO) as a co‐oxidant 10 Oxidative Cleavage to Carbonyl Products Periodate cleaves diols to give carbonyl groups: Ozonolysis accomplishes the same transformation (alkene to carbonyls) in one step! 11 Summary of Alkene Reactivity Reagent Stereoselective? HBr No X2 Yes (Anti) X2/H2O Yes (Anti) 1. Hg(OAc)2, H2O Depends on 2. NaBH4 reaction condns. 1. BH3 Yes (Syn) ( ) 2. H2O2, OH‐ H2, Pd/C Pd/C Yes (Syn) Yes (Syn) 1. OsO4 Yes (Syn) 2 NaHSO3, H 2. NaHSO H2O O 12 Regioselective? Yes (Markovnikov) ( ) N/A Yes (Markovnikov) Yes (Markovnikov) Yes (Non‐Markovnikov) ( k k ) N/A N/A Take‐Home Activity In-Class Problems Draw structures of the following three alkenes: Tip: You may want to review the naming principles in Chapter 7, Tip: You may want to review the naming principles in Chapter 7 sections 7.3‐7.5 (R,E)-3-ethyl-4-methylhept-2-ene (Z) 3 (Z)-3-methyloct-3-ene th l t 3 13 (E)-penta-1,3-diene Take‐Home Activity In-Class Problems H Ph Ph Ph OH + enantiomer , 3 O 4 S H a O 2 N H 2 ︶ O s O 1 ︶ HBr H2, Pd/C 1) O3 2) Zn/ HOAc Ph Br2, H2O Br2, CH2Cl2 HO Ph Ph 14 Review from 1st Year Organic Chemistry: g y The Chemistry of Alkyl Halides Chapter 10 ( (excluding 10.2‐10.4, 10.7 (only Gilman Reactions) g , ( y ) 15 Structure of Alkyl Halides Alkyl halide (R‐X): A compound containing a halogen atom covalently bonded to an sp3‐carbon atom The electronegative halogen polarizes the C‐X bond, resulting in an electron deficient (electrophilic) carbon atom 16 Preparation of Alkyl Halides: Two Main Methods 1) Reaction of alkenes with HX or X2 (discussed previously) 2) Reaction of alcohols ) a) with mineral acid (HCl or HBr) 3° b) with thionyl chloride (SOCl2) or phosphorus tribromide (PBr3): 1° or 2° 17 Reaction of Alkyl Halides: Grignard Reagents Alkyl (and alkenyl/aryl halides) (X = Cl, Br, I) react with magnesium to form organomagnesium halides (Grignard reagents): 18 The Grignard Reaction Reaction with Carbonyls R ti ith C b l Grignard reagents act as strong nucleophiles: The Grignard reaction is one of the most important The Grignard reaction is one of the most important carbon‐carbon bond forming reactions in organic chemistry 19 Gilman Reagents Gilman reagents (lithium diorganocopper) are similar in reactivity to Grignard reagents but use lithium and copper instead of magnesium and requires a 2 step process to make: magnesium and requires a 2‐step process to make: 1) alkyl halide alkyllithium 2) alkyllithium lithium diorganocopper (Gilman reagent) 20 Gilman Reagents Gilman reagents are also strong nucleophiles Gil l l hil that can form C‐C h f CC bonds with alkyl, alkenyl or aryl halides (X = Cl, Br, I): 21 In‐Class Problem Take‐Home Activity Draw structures for the following three alkyl halides: Tip: You may want to review the naming principles in Chapter 10, Tip: You may want to review the naming principles in Chapter 10 Section 10.1 3-ethyl-4,4-difluorooctane (E S)-6-bromohept-2-ene (E,S)-6-bromohept-2-ene (2S 4R)-1-chloro-4-iodo-2-methylhexane (2S,4R)-1-chloro-4-iodo-2-methylhexane 22 In‐Class Problem Take‐Home Activity Grignard reagents are generated and used in polar aprotic solvents including THF or diethyl ether. Explain why polar protic solvents like water or alcohols cannot be used solvents like water or alcohols cannot be used. 23 In‐Class Problem Take‐Home Activity Which of the following compounds cannot be used to generate Grignard reagents? Why? 24 In‐Class Problem Take‐Home Activity Design a synthesis of the secondary alcohol below using the two given starting materials as your only source of carbon: O OH + OH H 25