9-1 chapter 9 nucleophilic substitution -elimination 1. nucleophilic aliphatic substitution 2....

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9-3 Product(s) s Leaving group - stable with pair of e’ s, weak B: 9 Nucleophilic Substitution Nu: + R 3 C-X R 3 C-Nu + X: (-) conditions Reactions with Lewis :Bases / :Nucleophiles Conditions - solvent, temperature, etc

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9-1 Chapter 9 Nucleophilic Substitution & -Elimination 1. Nucleophilic Aliphatic Substitution 2. Solvents for Nucleophilic Substitution Reactions 3. Mechanisms of Nucleophilic aliphatic substitution 4. Evidence of S n 1 / S n 2 Mechanisms 5. Analysis of some Nucleophilic Substitution Rxs 6. -Elimination 7. -Elimination mechanism 8. Evidence for E1 and E2 9. Substitution vs Elimination 9-2 substitution - elimination rxs can compete leads to by-products (additional products) 4 9-3 Product(s) s Leaving group - stable with pair of e s, weak B: 9 Nucleophilic Substitution Nu: + R 3 C-X R 3 C-Nu + X: (-) conditions Reactions with Lewis :Bases / :Nucleophiles Conditions - solvent, temperature, etc 9-4 Nucleophilic Substitution (see Table 9.1 for more examples) Rx: (Chap 7) 4 9-5 Nucleophilic Substitution examples Table 9.1 continued 2 9-6 Nucleophilic Substitution examples Table 9.1 continued amine alcohol ether (after -H + ) 6 9-7 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant 15 5 9-8 A PROTIC PROTIC [H + ] NON-POLAR dielectric constant 15 5 DMSO 48.9 acetonitrile 37.5 DMF 36.7 acetone 20.7 dichloromethane 9.1 diethyl ether 4.3 toluene 2.3 hexane Solvents of reaction (rx) 9-9 water 79 formic acid 59 methanol 33 ethanol 24 acetic acid 6.2 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant 15 5 Substitution Mechanisms Difference: timing of bond-breaking and making One simultaneous breaking & making; [S N 2] Other, break then make bonds stepwise; [S N 1] 2 limiting mechanisms for substitution (S N 2, S N 1) 5 9-11 CHOBr H H H t.s. simultaneous bond breaking and making Mechanism - S N 2 sp 2 3 other products [important!] Mechanism - S N 1 4 9-13 S N reactions Reactant structure have on mechanism/rate? Structure of Nu: have on mechanism/rate? Leaving group have on rate? What effect does the: What is: The stereochemical course of S N reaction? The role of the solvent? When or why: Does rearrangement occur? 5 9-14 Kinetics/Nucleophilicity Kinetics/Nucleophilicity :Nucleophilicity - kinetic, speed of rxn. time Nu: C X H H H C Nu H H H + X (-) + - Nu: or B: H B-H + :Basicity - equilibrium Nucleophiles are also bases :Nucleophilicity and :Basicity have correlations 4 9-15 Reaction rate depends on [RX] unimolecular rx rate = k[(CH 3 ) 3 CBr] k - rate constant 1 st order kinetics / stepwise Kinetics - S N 1 4 9-16 both reactants in rate limiting step bimolecular reaction rate = k[ CH 3 Br ][ - OH ] 2 nd order kinetics CHOBr H H H kinetics - S N 2 9-17 rx profile: t.s. 1 t.s. 2 SM products prog of rx HH R+R+ SN1SN1 E t.s. SM products prog of rx HH SN2SN2 2 9-18 substitution S N 1 or S N 2? OR 2 9-19 S N 1 or S N 2 with a 2 o RX is on nucleophile nucleopilicity moderate strong weak strong bases 9-20 substitution S N 1 or S N 2? OR 9-21 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant 15 5 E + - Nu E+E+ - Nu polar 3 9-22 Solvents effects on Nu: - ProticAprotic The greater the the solvents dielectric constant, the better ions of opposite charge are separated. Polar and Nonpolar Solvents E + - Nu E+E+ - Nu polar 2 9-23 POLAR APROTIC solvents effective in solvating cations but poorly solvate anions, e.g.: Solvents effects on Nu: - The freer the Nucleophiles e (-) s the greater its Nucleophilicity 2 9-24 APROTIC solvents solvate cations F - free of Na + 3 9-25 A PROTIC PROTIC [H + ] NON-POLAR dielectric constant 15 5 DMSO 48.9 acetonitrile 37.5 DMF 36.7 acetone 20.7 solvents of S N 2 rx 9-26 PROTIC solvents solvate cations & anions e.g. CH 3 OH 2 9-27 S N 1rx on separating charges (+/-) in t.s. C CH 3 3 H 3 CCl Br (-) in solvent C CH 3 3 H 3 CBr rx rate THF* Acetone H 2 O - 4x10 3 *dielectric constant 7 protic polar solvents separate cations & anions 4 9-28 water 79 formic acid 59 methanol 33 ethanol 24 A PROTIC 2. Solvents PROTIC [H + ] NON-POLAR dielectric constant 15 5 9-29 Stereochemistry S N 1 4 9-30 Stereochemistry S N 2 - Stereochemistry S N 2 - inversion C CH 3 Br D H I C H 3 C I D H + Br acetone S R inversion of configuration S->R & R->S BUT... C CH 3 Br D H I - - t.s. backside attack, 5 9-31 S N 2 product is clearly inverted but substituent priorities changed S rotation product S backside attack, inversion of configuration 2 9-32 Structure of RX Structure of RX R 3 CX R 2 CHX RCH 2 X CH 3 X Reactivities for S N 1 and S N 2 opposite increasing stability of carbocation SN1SN1 SN2SN2 decreasing steric hindrance governed by steric factors governed by electronic factors 5 9-33 S N 2 sterics - 1 o :Nu (-) 3 o backside blocked S N 1 :Nu (-) 6 9-34 S N 2 sterics S N 2 sterics :Nu (-) 3 o backside blocked S N 1 5 9-35 hard to form easy to form RX - Carbocations (S N 1) RX - Carbocations (S N 1) 3 o R-X reacts by R + (S N 1) 3 9-36 (S N 1) Other Cations (S N 1) Other Cations allylic & benzylic cation - resonance stabilized - delocalizated (+) charge [S N 1] 1 o allylic 2 o alkyl o & 3 o allylic cations are even more sable (S N 1) Other Cations allylic & benzylic cation - resonance stabilized - delocalizated + charge [S N 1] 1 o allylic 9-38 mech. What is the effect of resonance on S N 1? same write either SN1SN1 rx 6 9-39 (S N 1) Other Cations (S N 1) Other Cations allylic & benzylic cation - resonance stabilized - delocalizated ( + ) - charge [S N 1] or hybrid 4 9-40 allylic (benzylic) facilitates S N 2 2 9-41 Leaving group X - gains e (-) s (Lewis base ) - less basic or more stable with e (-) s better leaving gp. e.g. (-) OH vs (-) Cl Nu: + R-X Nu R X Nu-R+ :X strong base neutral a s leaving gp Cl (-) > > > (-) OH 8 9-42 I (-) > Br (-) > Cl (-) ~ H 2 O > F (-) > AcO (-) > HO (-) > RO (-) > R 2 N (-) good leaving gp. stability of group with e (-) s special cases not leaving gp. Leaving group 9-43 Which of the given substrates would undergo S N 2 substitution? Product(s)? Reason? strong bases: (-) OH, (-) OCH 3 ; (-) NH 2 even stronger! not leaving groups 3 9-44 Other concerns - Rearrangements S N 1 yes (R+); S N 2 no 6 9-45 Summary of S N Rxs Alkyl Halide CH 3 X methyl S N 2S N 1 S N 1 does not occur. methyl cation too unstable SN2SN2 R 2 CHX secondary S N 1 favored with poor nucleophiles. S N 2 favored in with good nucleophiles RCH 2 X primaryNo S N 1, 1 cations rarely observed SN2SN2 Tertiary R 3 CX S N 2 does not occur; steric hindrance S N 1 - ease of formation of 3 o carbocations stereocenter substitution inversionracemization 4 9-46 polar protic unimolecular Guidelines for Substitution & Elimination H 3 C-X SN2SN2SN2SN2 weakweak S N 1 & E1 SN2SN2SN2SN2 Nu: - B: - polar aprotic bimolecular S N 1 & E1 weakweak B: - Nu: - med. B: good SN2SN2SN2SN2 Nu: - inversion racemic rearrange 8 9-47 S N 1/S N 2 Problems Predict: products, and show (arrows) the mechanism. SN2SN2 SN1SN1 11 9-48 a reaction in which a small molecule (HCl, HBr, HI, or HOH) is eliminated. -Elimination 9-49 E2: concerted break/make bonds bimolecular, rate [R-X] [ B: or (Nu:)] E1: break bond, then make bond unimolecular, rate [ R-X ] 2 limiting mechanisms for -elimination rx s -Elimination 9-50 Zaitsev rule: major -elimination product = the more stable alkene (more substituted). -elimination a a a b b b 9-51 Mechanisms (2) timing of bond breaking/making differs E2 9-52 E1 Mechanisms (2) timing of bond breaking/making differs E2 9-53 ionization, rate determining step (same as S N 1) E1 mechanism HH SM product progress of reaction R+R+ Eact t.s. 1 t.s. 2 3 9-54 E2 mechanism one-step mechanism; concerted bond-breaking and bond-forming t.s. SM products prog of rx HH 2 9-55 Stereoselectivity of E2 E2 most favorable (lowest Ea) - H and X are anti and coplanar 1 9-56 Stereoselectivity of E2 CC H H H R Bu t O - X H CC X - H H H R Bu t O H E2 most favorable (lowest Ea) - H and X are anti and coplanar 9-57 Regioselectivity of E1/E2 E1: major product is the more stable alkene E2: the major product is usually the more stable alkene, but on orientation of H and X (1.) (2.) *also S N 1 products how? 4 9-58 Stereochemistry of E1 (1.) (2.) 3 9-59 Stereochemistry of E2 The only anti-coplanar H to X arrangement forces formation of less stable olefin (2.) 9-60 E2 branching hinders S N 2 SN2SN2 6 9-61 S N vs E Many nucleophiles are also strong bases (OH - and RO - ), thus S N and E reactions often compete. 9-62 Guidelines for Substitution & Elimination H 3 C-X SN2SN2SN2SN2 E2 strong bulky ( t BuO - ) weakweak S N 1 & E1 weakweak B: - Nu: - E2 strong B: med. B: good SN2SN2SN2SN2 E2 strong B: - Nu: - SN2SN2SN2SN2 Nu: - B: - polar protic unimolecular polar aprotic bimolecular Nu: - inversion stereochem racemic rearrange 11