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

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 SubstitutionH 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

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