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

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. 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 Lecture Outline: Part 2

4. It was shown to be active against ovarian, breast, lung, pancreatic and other cancers.cancers 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.National Cancer Institute https://en.wikipedia.org/wiki/Paclitaxel The supply from the Pacific yew tree would not be enough. A need to synthesise it…. It was isolated from the bark of the Pacific yew tree, Taxus brevifolia, thus its name "taxol".Taxus brevifolia

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? Two atoms bonded by… …2 electrons 2 electrons ‘equally’ shared by two atoms

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

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

10. Lone Pairs Forming Bonds Bonding Electrons Forming Bonds ++ -- CH 3 H Br C H - OH CH 3 H OH C H Br - ethanol CH 3 H H H C C OH - CH 3 H H H C C BrH H OH Br - -- ++ ++ ++

11. Nucleophilic Substitution on a Saturated Carbon Electron rich Nucleophile (Nu) in search of an electron poor saturated carbon centre CH 3 H X C H Nu ++ -- Atom X is more electronegative than C AS Level

12. Nucleophilic Substitution: 1 12 ethanol CH 3 CH 2 Br+ OH - CH 3 CH 2 OH + Br - ( aqueous ) ++ -- CH 3 H Br C H - OH CH 3 H OH C H Br -

13. Nucleophilic Substitution: 2 propanenitrile CH 3 CH 2 I (ethanol)+ CN - (aq)CH 3 CH 2 CN + I - ++ -- CH 3 H Br C H CN - CH 3 H CN C H Br -

14. Nucleophilic Substitution: 3 aminoethane CH 3 CH 2 Br + NH 3 CH 3 CH 2 NH 2 2+ NH 4 + Br - ++ -- CH 3 H Br C H - H CH 3 H NH 2 C H + NH 3 CH 3 H NH 2 C H H NH 3 + Br -

15. It is found that there are two possible stereochemical outcomes, each described by a different rate equation, and different stereochemical outcomes. DescriptorRate EquationStereochemical Outcome S N 2rate = k[R-Hal][Nu]Inversion S N 1rate = k[R-Hal]Racemisation Stereochemistry Rate Equation Nothing is Black and White: 1

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

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

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

19. Nucleophilic Addition to Aldehydes/Ketones (C=O) Electron rich Nucleophile (Nu) in search of an electron poor unsaturated carbon centre Nu CH 3 C O ++ -- A2 Level

20. CH 3 COMe + HCN CH 3 C(OH)(CN)Me 2-hydroxy-2-methylpropanenitrile CH 3 CN C O CH 3 H H+H+ ++ -- CN CH 3 C O H C O + Nucleophilic Add’n to Aldehydes/Ketones 1 ++

21. 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 Nu CH 3 Cl C O ++ -- Then elimination of Cl - AS Level

22. + H 2 O CH 3 COOH+ HCl CH 3 COCl H2OH2O CH 3 Cl C O ++ -- CH 3 OH C O H + - Cl - CH 3 OH C O H + CH 3 OH C O HCl Nucleophilic Add’n to Acid Chlorides 1

23. + CH 3 NH 2 CH 3 CONHCH 3 + HCl CH 3 COCl RNH 2 CH 3 Cl C O ++ -- CH 3 NHR C O H + - Cl - CH 3 NHR C O H + CH 3 NHR C O HCl Nucleophilic Add’n to Acid Chlorides 1 N-methylethanamide An amide

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

25. Electrophilic Aromatic Substitution 1 C6H6C6H6 + HNO 3 /H 2 SO 4 C 6 H 5 NO 2 + H 2 O HNO 3 + 2H 2 SO 4 + 2HSO 4 - + H 3 O + NO 2 + Electrophile Nitronium Ion NO 2 O SO 3 H - + NO 2 H + H O SO 3 H catalyst

26. - Cl AlCl 3 Electrophilic Aromatic Substitution 2 C 6 H 6 + (CH 3 ) 2 CHCl C 6 H 5 CH(CH 3 ) 2 AlCl 3 CH 3 CH Cl CH 3 + CH 3 CH CH 3 CH(CH 3 ) 2 + H + HC CH 3 - Cl AlCl 3 + HCl Lewis acid Lewis Acid catalyst Secondary carbocation - Cl AlCl 3 + + AlCl 3

27. C6H6C6H6 + RCOCl C 6 H 5 COR+ HCl Lewis acid Electrophilic Aromatic Substitution 3 CH 3 C Cl O AlCl 3 - Cl AlCl 3 + CH 3 CO Acylium ion + H CH 3 C O - Cl AlCl 3 AlCl 3 H Cl + CH 3 CO C CH 3 O Not catalytic. Why?

28. Electrophilic Addition to Alkene CH 3 H H C C Electron rich  -bond in search of an electron poor electrophile (E) E AS Level

29. CH 3 CH=CHCH 3 + HBr CH 3 CH 2 CHBrCH 3 2-bromobutane CH 3 H H C C H H C C H + carbocation CH 3 H H C C BrH -- ++ H - Electrophilic Addition to an Alkene: 1 Permanent dipole

30. CH 3 CH=CHCH 3 + HOSO 3 HCH 3 CH 2 CH(OSO 3 H)CH 3 2-butylhydrogensulphate CH 3 H H C C OSO 3 H H ++ -- - carbocation CH 3 H H C C H + H H C C H OSO 3 H CH 3 Electrophilic Addition to an Alkene: 2

31. CH 3 CH=CH 2 + Br 2 CH 3 CHBrCH 2 Br 1,2-dibromopropane Br CH 3 H H H C C ++ -- H H H C C Br + - carbocation CH 3 H H H C C Br Induced Dipole Electrophilic Addition to an Alkene: 3

32. 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 B CH 3 H H H C C XH -- ++ ++ ++ AS Level

33. Elimination of HX: 1 CH 3 H H H C C OH - CH 3 H H H C C BrH propene H OH Br - CH 3 CHBrCH 3 + OH - CH 3 CH=CH 2 + H 2 O + Br - (in ethanol) acting as a base this time…. -- ++ ++ ++

34. CH 3 H H Cl C C HH -- ++ ++ ++ CH 3 H H H C C H H Nu C C HH B Nucleophilic Substitution Elimination of HX Cl - - - - BH Nothing is Black and White! 2

35. Free Radical Substitution of Alkanes Light Induced Radical Formation and Subsequent Replacement Reactions CH 3 ClCl H 3 CCl Cl AS Level

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

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

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

39. Radicals Consumed Chlorine Radical Reformed ClClH 3 CCl Cl H 3 CHCH 3 HCl Cl 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. Propagation

40. Radicals Consumed Radicals Not Reformed reaction of two radical species leading to nonradical products. Termination CH 3 Cl H 3 CCl CH 3 CH 3 H 3 C

41. CH 3 Cl + Cl 2 CH 2 Cl 2 + HCl CH 2 Cl 2 + Cl 2 CHCl 3 + HCl CHCl 3 + Cl 2 CCl 4 + HCl Further Free Radical Chlorination Reactions

42. CH 3 H X C H Nu CH 3 C O ++ -- Nu CH 3 Cl C O ++ -- Then elimination of Cl - CH 3 H H C C E E Nucleophilic Substitution Nucleophilic Addition Nucleophilic Addition-Elimination Electrophilic Addition Electrophilic Substitution Summary of the Chemistry Looked at

43. B CH 3 H H H C C XH -- ++ ++ ++ CH 3 ClCl H 3 CCl Cl Free Radical Substitution Elimination of HX

44. Chemistry at Birmingham www.chem.bham.ac.uk Chemistry at Birmingham Ranked in the first quartile of the 22 Russell Group Schools of Chemistry for student satisfaction and graduate employability Supporting women in Science

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