1. Chapter 22 Pericyclic Reactions
Bioorganic Chemistry
Spring 2006
Chapter 22 Pericyclic Reactions
a pericyclic reaction: formation/breaking of two or more bonds through
a concerted cyclic transition-state (generally non-polar)
BioorgChem-Chap22
Chapter 22

2. Pericyclic Reactions Highly stereospecific: concerted bond formation
Bioorganic Chemistry
Spring 2006
Pericyclic Reactions
Highly stereospecific: concerted bond formation
cycloaddition reactions: Diels-Alder reactions
electrocyclic reactions: conjugated polyenes;  957
sigmatropic & other concerted rearrangements
p MOs of conjugated molecules:  960, 962-3
No. of MOs = No. of component AOs
similar E difference relative to an isolated p orbital
E of an MO increases as the No. of node increases
nodes are symmetrically placed in an MO
BioorgChem-Chap22
Chapter 22

3. BioorgChem-Chap22

4. BioorgChem-Chap22

5. (antibonding)
(bonding)
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7. BioorgChem-Chap22

8. Cycloaddition Reactions (I)
Bioorganic Chemistry
Spring 2006
Cycloaddition Reactions (I)
Intermolecular pericyclic reactions giving a ring
No. of pi orbitals involved: [m+n] cycloaddition;  975
Theories of orbital (MO) interactions
favorable bonding interactions: stabilization of the total energy of the electrons → lower E of HOMO of product
favorable interaction between a HOMO and a LUMO
larger stabilization between similar energy levels
theories: FMO (frontier MO) theory by K. Fukui & orbital correlation analysis by R. B. Woodward and R. Hoffmann
BioorgChem-Chap22
Chapter 22

9. BioorgChem-Chap22

10. larger stabilization between orbitals of similar energy levels
BioorgChem-Chap22

11. frontier molecular orbital (FMO) theory by Fukui
orbital correlation method by Woodward & Hoffmann
[4p+2p]
p4* A
LUMO
antisymmetric (A) p*
LUMO
p3* S p2 A
HOMO
symmetric (S) p
HOMO p1 S
BioorgChem-Chap22

12. Cycloaddition Reactions (II)
Bioorganic Chemistry
Spring 2006
Cycloaddition Reactions (II)
[4+2] cycloaddition: thermally allowed;  977 top
facile reactions with substituents of opposite polarity
‘normal electron demand’ & ‘inverse electron demand’
[2+2] cycloaddition: thermally forbidden;  976 top
photochemically allowed: change of the ‘HOMO’:  977 mid.
odd e--pairs: thermal, even e--pairs: photochemical
Diels-Alder reactions: [4+2] cycloaddition
powerful tool for substituted cyclohexenes:  978
dienophiles (reactive) + dienes (reactive: s-cis)
BioorgChem-Chap22
Chapter 22

13. [4ps+2ps]
BioorgChem-Chap22

14. Change of the Energy Level by a Substituent (I)
“normal electron demand”
p4*
LUMO
p3*
LUMO p* p2
HOMO p1 p
HOMO
BioorgChem-Chap22

15. Change of the Energy Level by a Substituent (II)
“inverse electron demand”
LUMO p*
p4*
LUMO
p3* p
HOMO p2
HOMO p1
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16. BioorgChem-Chap22

17. Prohibited (Forbidden) Interactions
[2p+2p]
LUMO
LUMO p* A A S p S
HOMO
HOMO
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18. BioorgChem-Chap22

19. [2ps + 2ps]
HOMO
(SOMO)
LUMO p* p
HOMO
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20. high E
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21. Reactive Dienophiles
BioorgChem-Chap22

22. Reactive Dienes (I)
10 times faster
BioorgChem-Chap22

23. Reactive Dienes (II) retro-Diels-Alder reaction ‘do not react’
BioorgChem-Chap22

24. Cycloaddition Reactions (III)
Bioorganic Chemistry
Spring 2006
Cycloaddition Reactions (III)
Stereoselectivities in cycloaddition reactions
syn (cis) addition: stereospecific with the SMs
endo addition: dienophiles with pi bonds;  980
secondary p-p orbital interaction between the two p bonds
Regioselectivity: ‘ortho-like’/‘para-like’ products
C-1/C-2 substituents: mediocre selectivity;  982
Other important Diels-Alder reactions
aromatics as dienes/alkynes as dienophiles:  982-3
intramolecular/hetero Diels-Alder reaction:  983
BioorgChem-Chap22
Chapter 22

25. BioorgChem-Chap22

26. E D G + W -
BioorgChem-Chap22

27. BioorgChem-Chap22

28. inverse electron demand
BioorgChem-Chap22

29. Other Cycloaddition Reactions
Bioorganic Chemistry
Spring 2006
Other Cycloaddition Reactions
[2+2] cycloaddition under photo irradiation
cyclobutane rings: strained, hard to make;  984
Paterno-Büchi reaction: oxetanes;  985
thermal [2+2] cycloaddition: cis-cyclobutanones
ketenes [LUMO] + alkenes [HOMO]
Other cycloadditions: [8+2];  985
BioorgChem-Chap22
Chapter 22

30. BioorgChem-Chap22

31. BioorgChem-Chap22

32. [2ps+2pa]
BioorgChem-Chap22

33. Electrocyclic Reactions
Bioorganic Chemistry
Spring 2006
Electrocyclic Reactions
Intramolecular pericyclic reactions:  965 top
acyclic conjugated polyenes cyclic alkenes
[4n] e-: conrotation thermally allowed;  966 top
disrotation: photochemically allowed;  966 bottom
[4n+2] e-: disrotation thermally allowed;  967 top
conrotation: photochemically allowed;  967 bottom
practice: allowed? or forbidden? 
thermal reactions: equilibrium-controlled; 
photochemical reactions: irreversible;  970 bottom
Dewar benzene: an isomer of benzene; 
BioorgChem-Chap22
Chapter 22

34. BioorgChem-Chap22

35. BioorgChem-Chap22

36. trans-cyclobutene
(E,E)-diene
cis-cyclobutene
BioorgChem-Chap22

37. cis-cyclohexene
(E,Z,E)-triene
trans-cyclohexene
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39. BioorgChem-Chap22

40. BioorgChem-Chap22

41. BioorgChem-Chap22

42. [71 kcal/mole less stable]
BioorgChem-Chap22

43. [1962]
[1963]
BioorgChem-Chap22

44. Sigmatropic Rearrangements
Bioorganic Chemistry
Spring 2006
Sigmatropic Rearrangements
Intramolecular migration of a sigma bond:  986
along a pi system with rearrangement of the pi bond
[m,n] sigmatropic: No. of atoms broken; 
feasibility: HOMOs of two radicals;  988 middle
allowed only when both terminal overlaps are bonding
odd e--pairs: thermal, even e--pairs: photochemical;  988-9
[1,3]/[1,5] sigmatropic rearrangements:  990
[3,3]: Cope/Claisen rearrangements: 
stereoselectivity: chair-type TS mechanism
vitamin D3 from 7-dehydrocholesterol: 
BioorgChem-Chap22
Chapter 22

45. BioorgChem-Chap22

46. BioorgChem-Chap22

47. BioorgChem-Chap22

48. BioorgChem-Chap22

49. BioorgChem-Chap22

50. t1/2 = 1 h at 20 oC
BioorgChem-Chap22

51. Cope rearrangement: equilibrium-controlled
stable at -20 oC
BioorgChem-Chap22

52. Claisen rearrangement (I): Product favored
BioorgChem-Chap22

53. Claisen rearrangement (II): Product favored
BioorgChem-Chap22

54. Cope rearrangement: chair TS (I)
BioorgChem-Chap22

55. Cope rearrangement: chair TS (II)
BioorgChem-Chap22

56. Cope rearrangement: chair TS (III)
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57. Cope rearrangement: chair TS (IV)
BioorgChem-Chap22

58. [1,7] sigmatropic rearrangement thermally allowed
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59. BioorgChem-Chap22

60. Other Concerted Rearrangements
Bioorganic Chemistry
Spring 2006
Other Concerted Rearrangements
Pinacol rearrangement: 1,2-alkyl shift;  995
[1,2] sigmatropic shift to a carbocation: mechanism
Beckmann rearrangement: 1,2-shift;  996
R anti to OH of an oxime: caprolactam;  997
Hofmann rearrangement: amide with X2;  997
one less carbon homologation: RCO2H → RNH2
Curtius rearrangement: RCON3;  999
Baeyer-Villiger rearrangement:  998
ketones to esters / cyclic ketones to w-hydroxyesters
BioorgChem-Chap22
Chapter 22

61. BioorgChem-Chap22

62. BioorgChem-Chap22

63. caprolactam
raw material for nylon 6
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64. BioorgChem-Chap22

65. BioorgChem-Chap22

66. BioorgChem-Chap22