Baldwins Rules for Ring Closure

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Baldwins Rules for Ring Closure

• Dr Fabienne Pradaux
• Wednesday 2nd February 2005

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Baldwins Rules

• Qualitative set of generalization on the
  probability of a ring closure (RC)
• Empirical  rules  formulated from observations
  and stereoelectronic reasoning
• Describe kinetic feasibility of ring closure
• Physical basis lie in stereochemical
• The rules do not apply to second row elements and
  to pericyclic reactions

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Terminology/Classification (1)

• Prefix exo when the breaking bond is exocyclic to
  the smallest ring formed.
• Prefix endo when the breaking bond is endocyclic
  to the smallest ring formed.

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Terminology/Classification (2)

• Numerical prefix describe the size of formed
  ring.
• Sufixes Tet, Trig and Dig indicate the geometry
  of the carbon undergoing the RC.
• Tetrahedral for sp3 carbon
• Trigonal for sp2 carbon
• Digonal for sp carbon

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Rules for Ring Closure (1)

• Tetrahedral Systems
• 3 to 7-exo-Tet are all favoured processes
• 5 to 6-endo-Tet are disfavoured

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Rules for Ring Closure (2)

• Trigonal systems
• 3 to 7-exo-Trig are all favoured processes
• 3 to 5-endo-Trig are disfavoured 6 to
  7-endo-Trig are favoured

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Rules for Ring Closure (3)

• Digonal Systems
• 3 to 4-exo-Dig are disfavoured processes 5 to
  7-exo-Dig are favoured
• 3 to 7-endo-Dig are favoured

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Other Than Nucleophilic Cases

• Radical Processes (homolitic)
• Cationic Processes

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Attack Trajectories

• Favoured paths to transition states are

Tetrahedral Systems
Trigonal Systems
Digonal Systems
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Favoured and Disfavoured

• Favoured RC will be those in which length and
  nature of linking chain enables terminal atoms to
  achieve required trajectory to form final ring
  bond
• Disfavoured RC would require severe bond angle
  and distances distortion, so the desired RC will
  be difficult (if available, alternative pathways
  will dominate)

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Tetrahedral carbon (1)

• All exo-Tet cyclisations are favoured

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Tetrahedral carbon (2)

• Why all endo-Tet cyclisations are disfavoured?

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Trigonal Carbon (1)

• Why all exo-Trig cyclisations are favoured?

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Trigonal Carbon (2)

• Example of disfavoured 5-endo-Trig

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Trigonal Carbon (3)

• 5-endo-Trig versus 5-exo-Trig

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Trigonal Carbon (4)

• 5-endo-Trig exceptions

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Trigonal Carbon (5)

• 5-endo-Trig versus 5-exo-Trig Nitrogen analogue

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Trigonal Carbon (6)

• 5-endo-Trig versus 5-exo-Trig Nitrogen
  analogue (MO explanation)

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Digonal carbon

• All endo-Dig cyclizations are favoured

• 3- and 4-exo-Dig cyclisations are disfavoured

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Intramolecular Alkylations of Ketone Enolates (1)

• Endocyclic alkylations

• 6- to 7- membered RC
• Favoured
• 3- to 5- membered RC
• Disfavoured

• Exoclyclic alkylations

• 3- to 7- membered RC
• Favoured

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Intramolecular Aldol Condensations (1)

• Endocyclic reactions

• 3- to 5- membered RC
• Disfavoured
• 6- to 7- membered RC
• Favoured

• Exoclyclic reactions

• 3- to 7- membered RC
• Favoured

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Stereoelectronic Constraints
Intramolecular alkylations of ketone enolates
Intramolecular aldol condensations
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Intramolecular Alkylations of Ketone Enolates (1)

• Why 5-(Enolendo)-exo-tet disfavoured?

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Intramolecular Alkylations of Ketone Enolates (2)

• Why 6-(enolendo)-exo-tet favoured?

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Intramolecular Aldol Condensations (2)
6-(enolendo)-exo-trig versus 5-(enolendo)-exo-trig
Statistics 4 possibilities to form a 5 membered
ring 2 possibilities to form a
6 membered ring Previsions 6 membered ring
would be predominant or exclusive
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Intramolecular Aldol Condensations (3)
Formation of cyclohexanone totally dominates over
even statistically preferred cyclopentanones
production.
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Baldwin Rules in Harrity Group (1)

• Formation of cyclohexanones

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Baldwin Rules in Harrity Group(2)

• Formation of cyclobutane ketones

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Conclusion

• Only give information about whether processes are
  favoured or disfavoured and not allowed and
  forbidden.
• Nucleophilic RC feasibility strongly depends on
  ring size, geometry of reacting atom and exo or
  endo nature of reaction.
• Structural modification can dramatically affect
  the cyclization mode.
• If favoured trajectory of attack valid, then
  reaction will follow the Baldwins rules.

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Summary (1)
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Summary (2)
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References

• J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976,
  734.
• J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse,
  L. Silberman, R. C. Thomas, J. Chem. Soc., Chem.
  Commun. 1976, 736.
• J. E. Baldwin, R. C. Thomas, L. Kruse, L.
  Silberman, J. Org. Chem, 1977, 42, 3846.
• J. E. Baldwin, L. Kruse, J. Chem. Soc., Chem.
  Commun. 1977, 233.
• J. E. Baldwin, M. J. Lusch, Tetrahedron, 1982,
  38, 2939.
• C. D. Johnson, Acc. Chem. Res. 1993, 26, 476.
• J. Clayden, N. Greeves, S. Warren, P. Wothers,
  Oxford, chapter 42, p 1140.
• D. A. Evans, internet course.