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Organic Reaction Mechanisms

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Presentation on theme: "Organic Reaction Mechanisms"— Presentation transcript:

1 Organic Reaction Mechanisms
– Jon A Preece – Professor of Nanoscale Chemistry School of Chemistry, University of Birmingham West Midlands Chemistry Teaching Centre Haworth 101 2nd May 2017

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, Taxus brevifolia, 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….

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 ‘equally’ shared by two atoms
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 Electronegativty of atom A is less than atom B
Heterolytic Bond Cleavage A—B A B: A : B A B: Electronegativty of atom A is less than atom B

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

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

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

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

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

15 Nothing is Black and White: 1
Stereochemistry 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 Nucleophile can attacks from only one side of the chloroalkane
Nucleophilic Substitution: SN2 Nucleophile can attacks from only one side of the chloroalkane R 1 2 3 C l Rate = k [R-Hal][Nu] Nu Bimolecular Process Rate Determinig Step

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

19 The Nobel Prize in Chemistry 2016 was awarded jointly to Jean-Pierre Sauvage, Sir J. Fraser Stoddart and Bernard L. Feringa "for the design and synthesis of molecular machines".

20 5 nm State 1 -1e State R.A. Bissell, E. Córdova, A.E. Kaifer and J.F. Stoddart, Nature, 1994, 369,

21 http://www. birmingham. ac

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

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

24 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 CH3 Cl C O + Then elimination of Cl- Nu AS Level

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

42 Propagation C l H C C H H C l C l C l H C l
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 C l H 3 C C H 3 H C l C l C l H 3 C l Chlorine Radical Reformed

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

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

45 Summary of the Chemistry Looked at

46 - CH3 H X C - - CH3 C O CH3 Cl C O + + Nu Nu Nu CH3 H C X CH3 H C
Nucleophilic Substitution Nucleophilic Addition Nucleophilic Addition-Elimination CH3 H X C - - CH3 C O CH3 Cl C O + + Then elimination of Cl- Nu Nu Nu Electrophilic Substitution Electrophilic Addition Elimination of HX CH3 H C X CH3 H C + + E + E - B

47 Free Radical Substitution
H 3 l C l H 3 C C l

48 Supporting women in Science
Chemistry at Birmingham 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

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

52 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


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