West Midlands Chemistry Teaching Centre Haworth 101 26 th April 2016

1. Organic Reaction Mechanisms – Jon A Preece – Professor of Nanoscale Chemistry School of Chemistry, University of Birmingham j.a.preece@bham.ac.uk West Midlands Chemistry Teaching Centre Haworth 101 26th April 2016

2. Lecture Outline: Part 1 Context Why bother with Organic Reaction Mechanisms? What is a covalent bond? What are curly reaction mechanism arrows and what is their physical meaning? How do we form bonds with pairs of electrons (lone pairs or bonding electron pairs)?

3. Lecture Outline: Part 2 Organic Reaction Mechanisms Nucleophilic substitution with haloalkanes Nucleophilic addition with aldehydes/ketones Nucleophilic substitution (addition-elimination) with acid chlorides Electrophilic aromatic substitution Electrophilic addition to alkenes Elimination of HX from haloalkanes (X = halogen) Free radical chlorination of alkanes

4. Why Are We Interested In Organic Reaction Mechanisms Paclitaxel was discovered beginning in 1962 as a result of a U.S. National Cancer Institute-funded screening program. It was isolated from the bark of the Pacific yew tree, Taxusbrevifolia, thus its name "taxol". It was shown to be active against ovarian, breast, lung, pancreatic and other cancers. The supply from the Pacific yew tree would not be enough. A need to synthesise it…. https://en.wikipedia.org/wiki/Paclitaxel

5. 53 Step Synthesis!! We need to bring understand at a molecular level (mechanism), in order to: 1. understand chemical transformations, 2. enabling the development of even more complex chemistry, and 3. to allow new drugs and materials to be designed and synthesised.

6. Molecules are 3D Objects

7. What is a Covalent Bond? 2 electrons ‘equally’ shared by two atoms Two atoms bonded by… …2 electrons

8. Reaction Mechanism ‘Curly’ Arrows Two Electron Movement Double headed arrow

9. Heterolytic Bond Cleavage A—B A B: A : B A B: Electronegativty of atom A is less than atom B

10. H - + OH C CH3 H H H H - - - C C OH Br Br Br C CH3 CH3 H - H OH H H H OH C C H CH3 Br H Lone Pairs Forming Bonds ethanol Bonding Electrons Forming Bonds + + + -

11. + - H X C CH3 H Nu Nucleophilic Substitution on a Saturated Carbon Electron rich Nucleophile (Nu) in search of an electron poor saturated carbon centre Atom X is more electronegative than C AS Level

12. H - + OH C CH3 H H - Br Br C CH3 - H OH Nucleophilic Substitution: 1 CH3CH2Br + OH- (aqueous) CH3CH2OH + Br- ethanol

13. H + - CN C CH3 H H - Br Br C CH3 H - CN Nucleophilic Substitution: 2 CH3CH2I (ethanol) + CN-(aq) CH3CH2CN + I- propanenitrile

14. - Br - + H NH3 + H H NH3 NH2 Br C C CH3 CH3 H H H - H NH3+Br NH2 C CH3 H Nucleophilic Substitution: 3 CH3CH2Br + NH3 2 CH3CH2NH2 + NH4+Br- aminoethane

15. Stereochemistry Nothing is Black and White: 1 Rate Equation It is found that there are two possible stereochemical outcomes, each described by a different rate equation, and different stereochemical outcomes. Descriptor Rate Equation Stereochemical Outcome SN2 rate = k[R-Hal][Nu] Inversion SN1 rate = k[R-Hal] Racemisation

16. Bimolecular 1 R Process C l 3 R Rate = k [R-Hal][Nu] 2 R Rate Determinig Step Nucleophilic Substitution: SN2 Nucleophile can attacks from only one side of the chloroalkane Nu

17. http://chemistry.boisestate.edu/rbanks/organic/sn2.gif

18. Carbocation 1 Unimolecular R 1 R Process C l 3 R 2 2 Rate = k [R-Hal] 3 R R R Rate Determining State 1 R N u 3 R 2 R 1 R N u 3 R 2 R One enantiomer Racemisation Nucleophilic Substitution: SN1 Nucleophile attacks from either side of the carbocation with equal probability. Cl Nu Nu

19. O C CH3 CH3 Nu Nucleophilic Addition to Aldehydes/Ketones (C=O) - Electron rich Nucleophile (Nu) in search of an electron poor unsaturated carbon centre + A2 Level

20. O O O H C C CH3 CH3 C CH3 CH3 CH3 CH3 CN CN Nucleophilic Add’n to Aldehydes/Ketones 1 + HCN CH3COMe CH3C(OH)(CN)Me 2-hydroxy-2-methylpropanenitrile + H+ - H + +

21. O C CH3 Cl Nu Nucleophilic Addition to Acid Chlorides (R(Cl)C=O) Followed by Elimination - Electron rich Nucleophile (Nu) in search of an electron poor unsaturated carbon centre + Then elimination of Cl- AS Level

22. O O O C C C CH3 CH3 CH3 Cl OH OH H2O Nucleophilic Add’n to Acid Chlorides 1 CH3COCl + H2O CH3COOH + HCl - O - + C Cl CH3 + - H OH + Cl H HCl

23. O O O C C C CH3 CH3 CH3 Cl NHR NHR RNH2 Nucleophilic Add’n to Acid Chlorides 1 CH3COCl + CH3NH2 CH3CONHCH3 + HCl N-methylethanamide - O - + + C Cl CH3 + - H NHR Cl H An amide HCl

24. + E Electrophilic Aromatic Substitution Electron rich aromatic unit in search of an electron poor electrophile (E) A2 Level

25. NO2 H + + NO2 O SO3H- + NO2 NO2 H O SO3H Electrophilic Aromatic Substitution 1 C6H6 + H2O + HNO3/H2SO4 C6H5NO2 + H3O+ HNO3 + 2H2SO4 + 2HSO4- Electrophile Nitronium Ion catalyst

26. - - - Cl AlCl3 Cl AlCl3 Cl AlCl3 CH(CH3)2 H + CH(CH3)2 CH3 CHCl Electrophilic Aromatic Substitution 2 Lewis acid C6H6 + (CH3)2CHCl C6H5CH(CH3)2 + HCl AlCl3 + CH3 CH + Lewis Acid catalyst CH3 Secondary carbocation CH3 + AlCl3 + HC CH3 CH3 + HCl

27. - - Cl AlCl3 Cl AlCl3 O CH3C H Cl O + + CH3C CH3C O O CH3C H + Cl Electrophilic Aromatic Substitution 3 Lewis acid C6H6 + RCOCl C6H5COR + HCl CH3 C O AlCl3 Acylium ion Not catalytic. Why? AlCl3

28. CH3 H C C CH3 H E Electrophilic Addition to Alkene Electron rich p-bond in search of an electron poor electrophile (E) AS Level

29. CH3 H C C H H CH3 H CH3 C C CH3 + + H H - Br Br H H - CH3 C C CH3 Br H Electrophilic Addition to an Alkene: 1 CH3CH2CHBrCH3 CH3CH=CHCH3 + HBr 2-bromobutane carbocation Permanent dipole

30. H H C C H H CH3 CH3 CH3 C C CH3 + + H H - OSO3H OSO3H H H - CH3 C C CH3 H OSO3H Electrophilic Addition to an Alkene: 2 CH3CH=CHCH3 + HOSO3H CH3CH2CH(OSO3H)CH3 2-butylhydrogensulphate carbocation

31. H H C C H H CH3 H C C H CH3 + Br - Br Br Br + Br Br H H - C C H CH3 Br Br Electrophilic Addition to an Alkene: 3 CH3CH=CH2 + Br2 CH3CHBrCH2Br 1,2-dibromopropane carbocation Induced Dipole

32. B H H C C H CH3 X H Elimination of HX from Alkanes to form an alkene Lone Pair of Electrons on Base (B:)in search of an electron poor hydrogen centre + + + - Atom X is more electronegative than C AS Level

33. H H - - C C OH Br CH3 H H H H OH C C H CH3 Br H Elimination of HX: 1 CH3CH=CH2 + H2O + Br- + OH- CH3CHBrCH3 (in ethanol) propene + + + - acting as a base this time….

34. H H C C CH3 H Nu H H H H B C C C C Cl Nu CH3 CH3 H H H H Nothing is Black and White! 2 Nucleophilic Substitution - - - BH Cl Cl - + + + - Elimination of HX

35. C l C H C l C l H C C l 3 3 Free Radical Substitution of Alkanes Light Induced Radical Formation and Subsequent Replacement Reactions AS Level

36. Reaction Mechanism ‘Curly’ Arrows One Electron Movement Single ‘fish hook’ headed arrow

37. Homolytic Bond Cleavage C—D C• D• C : D C• D• Electronegativty of atom A is usually similar to atom B

38. Light C l C l C l C l Initiation the formation of chlorine radicals by the homolytic bond cleavage of diatomic chlorine, induced by light. Radicals Formed

39. H C C l C H H C l 3 3 C l C l C l H C C l 3 Propagation reaction of the chlorine radicals with methane, which generates methyl radicals and HCl. Followed by the methyl radicals reacting with diatomic chlorine, to afford chloromethane and a chlorine radical. Radicals Consumed H Chlorine Radical Reformed

40. C C H H C l H H C C CH3 C l CH3 3 3 3 3 Termination reaction of two radical species leading to nonradical products. Radicals Consumed Radicals Not Reformed

41. Further Free Radical Chlorination Reactions CH3Cl + Cl2 CH2Cl2 + HCl CH2Cl2 + Cl2 CHCl3 + HCl CHCl3 + Cl2 CCl4 + HCl

42. CH3 H C C CH3 H O O H C C CH3 CH3 X C CH3 CH3 Cl E H Nu Nu Nu Nucleophilic Substitution Nucleophilic Addition Nucleophilic Addition-Elimination - - + + Then elimination of Cl- Electrophilic Addition Electrophilic Substitution Summary of the Chemistry Looked at E

43. B C l C H C l C l H C C l 3 3 H H C C H CH3 X H Free Radical Substitution Elimination of HX + + + -

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45. Concluding Comments Is the reaction light induced? No Yes Look for a bond with little or no electronegativity difference in a bonded pair of atoms Identify bonds with large differences in electronegativity in a bonded pair of atoms. Identify polarity to identify electrophilc centre Initiate: Cleave bond homolytically Propagate: generate new radicals Identify nucleophilic centre in other reagent (lone pair of electrons) or bonded pair of electrons to donate to electrophilic centre terminate: react radicals together