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Alkyl halides, Alcohols, Ethers, Thiols Required background: Acidity and basicity Functional groups Molecular geometry and polarity Essential for: 1. Chemistry of carbonyl compounds 2. Reactions under basic conditions 3. Chemistry of acetals and ketals Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry C C Both carbons are additionally connected only to either carbons, or hydrogens O Ethers sp3 C A hydroxy-group, attached to a sp3-hybridized carbon (except for vinyl alcohols) OH Alcohols C 1 C C C o C X 2o C C 3o C X X C A primary compound A secondary compound A tertiary compound This classification does not work for amines! Example: CH3CH2Br - a primary bromide Substitution of oxygen with sulfur in alcohols leads to thiols Substitution of oxygen with sulfur in ethers leads to sulfides Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry 1. Addition of Hal2 or HHal to alkenes (see unit “Alkenes”) 2. Radical halogenation of alkanes a. Chain initiation Cl2 = 2Cl. (requires irradiation by light or high temperatures) b. Chain propagation RH + Cl. = R. + HCl; R. + Cl2 = RCl + Cl. c. Chain termination 2Cl. = Cl2; 2R. = R2; R. + Cl. = RCl Br2 reacts like Cl2, but it is less reactive and more selective. I2 does not react this way, because I. is too stable to split the C-H bond. F2 is so reactive that it breaks both C-H and C-C bonds: 7F2 + C2H6 = 2CF4 + 6HF Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry Terminology of nucleophilic substitution (in general) R1 R1 R2 X + R2 Nu- R3 R3 Substrate Leaving group Substitution Nucleophile SN1 Nucleophilic First overall order v = k[substrate] Nu + X- R2 R1 R2 X R3 R1 + C Nu- R3 NuR1 R1 R2 R3 R2 Nu Nu 1 : 1 ratio (a racemic mixture) The SN1 mechanism takes place: 1. For tertiary substrates – always 2. For secondary substrates – sometimes 3. For primary substrates - never R3 Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry R2 R1 Nu- R2 R3 X - Nu R1 + C R1 R2 X- Nu + R3 R3 100 % inversion of configuration V = k[substrate][Nu-] The SN2 mechanism takes place: 1. For tertiary substrates – never 2. For secondary substrates – sometimes 3. For primary substrates - always X- Nucleophilicity is the ability to donate a pair of electrons to a non-hydrogen atom. Nucleophilicity depends on the ability of the nucleophile to donate a pair of electrons to H+ (basicity) and on the influence on such ability from the substrate (usually polarizability). Polarizability is characteristic for large atoms and greatly increases nucleophilicity. - HO H2O Basicity Nucleophilicity - I Br - Cl - - F Basicity Nucleophilicity Weaker bases make better leaving groups. Factor Stability of carbocation Steric hindrance Nucleophilicity Good leaving group SN1 SN2 + No effect No effect - No effect + + + SN1 reactivity Primary substrates Secondary substrates SN2 reactivity Tertiary substrates H3C H3C OH NaCl Cl H3C H3C CH3 CH3 No reaction Cl CH3 + C H3C + - - HO Very bad leaving group CH3 How to improve the leaving group? Make it neutral (decrease its basicity) H3C H3C HCl OH Cl H3C H3C CH3 CH3 + S N1 H Cl CH3 H3C - H + + O H3C C H CH3 + H2O Good leaving group H3C CH3 Cl - CH 2 NaCl OH CH 2 H3C H3C Cl + - HO Very bad leaving group No reaction CH 2 HCl OH CH 2 H3C Cl H3C + SN 2 H - H2O Cl - H CH 2 H3C + Good leaving group O H Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry Regioselectivity of E2 H H2C CH3O- CH 2 H3C CH 2 CH3 H H3C CH3 CH3 Br Minor product CH3O- H Major product Reminder: Alkoxides are stronger bases, than OH- due to weaker solvation This is another example of the Zaitsev’s rule. Elimination 2nd order E2 Elimination E2 requires a strong base CH 2 Br CH 2 H2C CH2 + Br - + H2O H - HO OH- is a stronger base in ethanol, than in water, because it is solvated less Competing reactions SN2 E2 Basicity of the attacking group Nucleophilicity of the attacking group R1 R1 + X R2 H C R1 C R2 C C C R2 H Common rate limiting step for E1 and SN1 Y- Nucleophilicity and basicity of Y- do not affect the reactions E1 and SN1, because Y- is not involved in the rate limiting step. Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry Chloroform (CHCl3) and dichloromethane (CH2Cl2) are non-flammable organic solvents Tetrachloroethylene, trichloroethylene are dry-cleaning solvents Herbicides and pesticides: Refrigerants (chlorofluorohydrocarbons) Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry In a polar solution, acidity of alcohols is lower, than acidity of water due to the less efficient solvation of the alkoxides (steric reason). Stronger base CH3CH2OH + OH- Stronger acid CH3CH2O- + H2O pKa = 15.9 pKa = 15.7 An alkoxide Primary alcohols Secondary alcohols Tertiary alcohols Acidity CH3CH2OH, pKa = 15.9 Primary alcoxides CH3CH(OH)CH3, pKa = 17.1 (CH3)3COH, pKa = 19.2 Secondary alcoxides Tertiary alcoxides Basicity Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry 1. Dehydration H3C H3C CH3 H+ CH3 OH H3C H3C - H+ + H E1 H H3C CH3 + O H3C H3C C H + CH3 H H3C Zaitsev’s rule: During elimination hydrogen is eliminated from the least hydrogenated carbon The Zaitsev’s rule controls regioselectivity of elimination and based on different stability of transition states with partial double bonds Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry 1a. Williamson Synthesis (SN2) R1-O- + R2-I R1-O-R2 + I- For primary R2 the reaction works the best For secondary R2 the reaction works, but elimination takes place as well For tertiary R2 the reaction almost never works. Only competing elimination takes place. - O Na CH3 + O + Ph CH 3 I CH3 Ph CH3 90% 90% 1b. Alcoholysis (SN1) H3C H3C + CH3 CH3 H3C Br O H3C OH H2C CH3 H3C + CH3 CH3 Minor product (E1) Major product (SN1) These reactions are also used to synthesize sulfides. Ts OHH3C SH H3C H3C - S O H3C S CH3 H2SO4, 140 oC .. OH .. H3C H3C O CH3 + H H .. H .. + H3C O .. O CH3 H + H3C SN2 O CH3 H For primary and secondary alcohols the reaction requires drastic conditions. For tertiary alcohols the reaction changes mechanism and proceeds under much milder conditions. H3C .. OH .. H3C H3C C2H5OH, dilute H2SO4 + H H3C O CH3 H3C H3C H H3C + H3C H3C H3C H .. O H3C + H3C O H H3C SN 1 H .. H3C ..O + C H3C CH3 CH3 1. Protonation H .. ..O R + ..O + H R R R Oxonium (soluble in water) F .. ..O H5C2 b.p.~36 oC C2H5 + F F F B B F F gas O H5C2 C2H5 b.p.~110 oC Outline 1. Structures of alkyl halides, alcohols, and ethers 2. Synthesis of alkyl halides 3. SN1 reaction 4. SN2 reaction 5. E1, E2 reactions 6. Applications of alkyl halides 7. Acidity and basicity of alcohols 8. Dehydration of alcohols 9. Synthesis of ethers 10. Solvents in organic chemistry