CHEM 232 University of Illinois Organic Chemistry I at Chicago UIC Lecture 28 Organic Chemistry 1 Professor Duncan Wardrop April 22, 2010 1 Today’s Lecture Topics Covered: 1. Aryl Halides - Bonding, Physical Properties and Reactions 2. Nucleophilic Aromatic Substitution of Chlorobenzene 3. Nucleophilic Aromatic Substitution: Addition-Elimination 4. Floxcin - Application of Nucleophilic Aromatic Substitution 5. Nucleophilic Aromatic Substitution: Elimination-Addition 2 What’s the Difference Between Ar- and Ph-? Phenyl refers specifically to this: Aryl is a general term for all aromatic ring systems: C N N O 3 Chapter 23 Aryl Halides 4 23.1 Bonding in Aryl Halides 5 Aryl Halides X Aryl halides are halides in which the halogen is attached directly to an aromatic ring. Carbon-halogen bonds in aryl halides are shorter and stronger than carbon- halogen bonds in alkyl halides. 6 Dissociation Energies of Selected Compounds Bond Energy: kJ/mol (kcal/mol) X = H X = Cl CH3CH2X sp3 410 (98) 339 (81) 2 H2C CHX sp 452 (108) 368 (88) X sp2 469 (112) 406 (97) 7 Resonance Picture X X X H H C-X bonds in aryl halides have more double bond character than C-X bonds in alkyl halides 8 23.2 Sources of Aryl Halides 9 Preparation of Aryl Halides Halogenation of arenes (Section 12.5) H Br FeBr3 Br2 HBr electrophilic aromatic substitution 10 Preparation of Aryl Halides The Sandmeyer reaction (Section 22.17) N H H N N Cl Cl NaNO2 CuCl O HCl, H2O O heat O N+ N+ N+ O– O– O– Primary Aryl Diazonium Aryl Chloride Arylamine Salt diazotization-nucleophilic aromatic substitution 11 Preparation of Aryl Halides The Schiemann reaction (Section 22.17) N H H N BF4 N F 1. NaNO2 HCl, H2O H2O 2. HBF4 heat Me Me Me O O O Primary Aryl Diazonium Aryl Fluoride Arylamine Salt diazotization-nucleophilic aromatic substitution 12 Preparation of Aryl Halides Reaction of aryl diazonium salts with iodide ion (Section 22.18) N H H N Cl N I Me Me Me NaNO2 KI HCl, H O room 2 temp. Primary Aryl Diazonium Aryl Iodide Arylamine Salt diazotization-nucleophilic aromatic substitution 13 23.3 Physical Properties of Aryl Halides 14 Physical Properties of Aryl Halides resemble alkyl halides are essentially insoluble in water less polar than alkyl halides Cl Cl µ 2.2 D µ 1.7 D 15 23.4 Reactions of Aryl Halides: A Review and a Preview 16 Reactions Involving Aryl Halides Electrophilic aromatic substitution (Section 12.14) Br Br Br Br BrOH (hypobromous acid) Br Br Bromobenzene Br 35.7% 1.0% 64.3% halide substituents are ortho-para directing & deactivating 17 Reactions Involving Aryl Halides Electrophilic aromatic substitution (Section 12.14) ADD DDT SYNTHESIS 18 Reactions Involving Aryl Halides Formation of aryl Grignard reagents (Section 14.4) Br MgBr Mg Et2O Bromobenzene Phenylmagnesium bromide 19 Substitution Reactions Involving Aryl Halides We have not yet seen any nucleophilic substitution reactions of aryl halides. Nucleophilic substitution on chlorobenzene occurs so slowly that forcing conditions are required. 20 Nucleophilic Substitution of Chlorobenzene Cl OH 1. NaOH, H2O 370°C 2. H+ (97%) This reaction does not proceed via SN2…….. 21 Why is Chlorobenzene Unreactive? the SN2 is not reasonable because the aromatic ring blocks back-side approach of the nucleophile. Inversion is not possible. 22 SN1 Also Unlikely: Aryl Cations are Highly Unstable empty sp2 orbital Cl S 1 N C + Cl Aryl Cation SN1 not reasonable because: 1) C—Cl bond is strong; therefore, ionization to a carbocation is a high-energy process 2) aryl cations are highly unstable 23 SN1 Reaction is Possible with Very Powerful Leaving Groups such as Dinitrogen N N OH C SN1 H2O Aryl Cation This is a unique case: halides are not good enough leaving groups for this process to occur. 24 What is the Mechanism of This Reaction? Cl OH 1. NaOH, H2O 370°C 2. H+ (97%) 25 23.5 Nucleophilic Substitution in Nitro-Substituted Aryl Halides 26 Nucleophilic Aromatic Substitution (SNAr)? H H E -H+ E E Electrophilic Aromatic Substitution X X Nuc -X- Nuc Nuc Nucleophilic Aromatic Substitution? 27 Electron-Deficient Haloarenes Undergo Nucleophilic Aromatic Substitution In contrast to chlorobenzene, nitro-substituted aryl halides undergo nucleophilic aromatic substitution at reasonable temperatures Cl OCH3 CH3OH + NaOCH3 + NaCl 85°C NO2 NO2 (92%) 28 The More Electron-Deficient the Haloarene, the Faster the Substitution Cl Cl Cl O O– Cl O N+ N+ N+ O– O O– N+ N+ N+ –O O –O O –O O 1.0 7 x 1010 2.4 x 1015 too fast to measure 29 Direct Displacement Doesn’t Occur! Br Nuc Nuc: 30 Kinetics of Nucleophilic Aromatic Substitution follows second-order rate law: rate = k [aryl halide] [nucleophile] inference: both the aryl halide and the nucleophile are involved in rate-determining step 31 Effect of Leaving Group Upon Rate of SN2 During SN2 reactions, the C-X bond breaks during the rate-determining step R' R' R' − δ+ δ C Nuc C X C R R'' Nuc R'' X R R'' R Reaction Rate Depends on X: I > Br > Cl > F C-F (485 kJ/mol), C-Cl (327 kJ/mol) C-Br (285 kJ/ml, C-I (213 kJ/mol) 32 Effect of Leaving Group in Nucleophilic Aromatic Substitution X Relative Rate* X F 312 Cl 1.0 Br 0.8 NO2 I 0.4 *NaOCH3, CH3OH, 50°C C-F (485 kJ/mol), C-Cl (327 kJ/mol) C-Br (285 kJ/ml, C-I (213 kJ/mol) 33 General Features of Mechanism 1. bimolecular rate-determining step in which nucleophile attacks aryl halide 2. rate-determining step precedes carbon-halogen bond cleavage 3. rate-determining transition state is stabilized by electron-withdrawing groups (such as NO2) 34 23.6 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution 35 Addition-Elimination Mechanism Two step mechanism: Step 1 nucleophile attacks aryl halide and bonds to the carbon that bears the halogen (slow: aromaticity of ring lost in this step) Step 2 intermediate formed in first step loses halide (fast: aromaticity of ring restored in this step) 36 Addition-Elimination Mechanism F OCH3 CH3OH + NaOCH3 + NaF 85°C NO2 NO2 (92%) 37 Addition-Elimination Mechanism Step 1 - Addition bimolecular CH3 O consistent with second- F order kinetics; first order in aryl halide, first order in nucleophile NO2 Rate = k [CH3ONa] [arene] 38 Addition-Elimination Mechanism Step 1 - Addition CH3 O F CH3O F H Slow NO2 NO2 39 Reaction Involves an Anionic Intermediate intermediate is negatively CH3O F charged H formed faster when ring bears electron-withdrawing groups such as NO2 because negative charge is stabilized…….. N O O 40 Stabilization of Addition Product by Electron-Withdrawing Group CH3O F CH3O F H H N N O O O O 41 Rapid Collapse of Cyclohexadienyl Anion Intermediate Step 2 - Elimination OCH3 CH3O F H Fast F N NO2 O O 42 The Role of Leaving Groups F > Cl > Br > I is unusual, but consistent with mechanism carbon-halogen bond breaking does not occur until after the rate-determining step electronegative F stabilizes negatively charged intermediate 43 The Role of Leaving Groups Nuc F Nuc Cl Nuc Br Nuc I H H H H N N N N O O O O O O O O Most Stabilized Least Stabilized 44 23.7 Related Nucleophilic Aromatic Substitution Reactions 45 Substitution of Hexafluorobenzene F OCH3 F F F F NaOCH3 (72%) CH3OH F F 65°C F F F F Six fluorine CH3O F substituents stabilize F F negatively charged intermediate formed in rate-determining step F F and increase rate of F nucleophilic aromatic substitution. Anionic Intermediate 46 Substitution of 2-Chloropyridine NaOCH3 CH3OH N Cl 50°C N OCH3 2-Chloropyridine reacts 230,000,000 times faster than chlorobenzene under these conditions. 47 Substitution of 2-Chloropyridine O CH3 Nitrogen is more NaOCH3 electronegative than carbon, stabilizes CH OH 3 N OCH the anionic N Cl 50°C 3 intermediate, and increases the rate at which it is formed. OCH3 N Cl Anionic Intermediate 48 Compare 2-Chloropyridine with Chlorobenzene NaOCH3 CH3OH N Cl 50°C N OCH3 1. NaOH, H2O 370°C + Cl 2. H OH 49 Synthetic Application of Nucleophilic Aromatic Substitution 50 Ofloxacin H O O Ofloxacin (trade F name Floxin) is OOHEt a broad- spectrum N N quinolone N O Me antibiotic Me H Ofloxacin http://www.ofloxacin.com/ 51 Synthesis of Ofloxacin, Part 1 H O O H O O 1,4-Addition F F OEt OEt OMe F F OMe F F HN F NH F 2 OH Me OH -MeO Me Elimination H O O F OEt F F NH F OH Me 52 Synthesis of Ofloxacin, Part 2 H O O H O O Addition F F OEt OEt F F F N NH F F F OH OH Me Me Elimination Nucleophilic Aromatic H O O Substition F OEt F N F OH Me 53 Synthesis of Ofloxacin, Part 3 H O O H O O Addition F F OEt OEt F N F N F F Me HO Me O H H -F Elimination Nucleophilic H O O Aromatic Substition F OEt F N O Me H 54 Synthesis of Ofloxacin, Part 4 H O O H O O Addition F F OEt OEt F F N N N Me O O Me NH H H N N Me Me Elimination Nucleophilic Aromatic H O O Substition F OEt N N N O Me Me H 55 Synthesis of Ofloxacin, Part 5 H O O F OEt N N Me NaOH N O H O Me 2 H H O O F OH N N N O Me Me H Ofloxacin 56 Synthetic Application of Nucleophilic Aromatic Substitution 57 Page 238 Furosemide Ofloxacin (trade name Floxin) is a broad- spectrum quinolone antibiotic Prozac another Ofloxacin good idea http://www.ofloxacin.com/ 58 23.8 Benzyne & the Elimination- Addition Mechanism of Nucleophilic Aromatic Substitution 59 Aryl Halides Undergo Substitution When Treated With Very Strong Bases Cl NH2 KNH2, NH3 (52%) -33 °C Ammonia: pKa = 34; b.p.