Baldwin’s Rules Nadia Fleary-Roberts 02/05/12

Baldwin’s rules for ring closure Proposed in 1976 by Sir Jack Baldwin Guidelines for ring closing reactions of 3- to 7-membered rings- empirical rules derived from experimental observations J. Chem. Soc. Chem. Commum., 1976, 734-736 Advanced organic chemistry, March p 212 Clayden 1st Edn p 1140 2nd Edn p 810 Dr. F. Pradaux, Sheffield University

Nomenclature 1. Ring size 3, 4,......7 Number Indicates the size of the ring being formed

Nomenclature 2. Bond The bond broken as the ring is formed is outside the new ring The bond broken as the ring is formed is inside the ring

Nomenclature 3. Geometry geometry of the carbon undergoing the ring closing can be describes as: sp3 tetrahedral carbon tet sp2 trigonal carbon trig sp digonal carbon dig

For example.....

Reactions can be favoured or disfavoured kinetic favourability of a reaction A disfavoured reaction does not mean that the reaction will not occur -just that it is more difficult Disfavoured cases require severe distortion of bond angles and distances

Ideal bond angles Favoured cyclisations enable terminal atoms to achieve proper geometries Trigonal carbons (Bürgi-Dunitz) Tetrahedral carbons (Walden inversion) Digonal carbons

Tetrahedral systems all exo-tet cyclisations are favoured

Trigonal systems All exo-trig cyclisatons are favourable 5-endo trig are disfavoured!

Favoured exo-tet and exo-trig

Disfavoured 5-Endo-trig

Disfavoured 5-Endo-trig...iodocyclisation Iodocyclisation forms the disfavoured “anti-Baldwin” endo-trig product WHY? Overwhelming attraction between nucleophile and electrophile No kinetically favoured alternative pathways- 4-exo-tet would be too strained Knight et.al. Tetrahedron Lett. 1998, 39, 8909

however 5-exo-trig strongly favoured over the 5-endo-trig

Digonal systems All endo-dig are favoured

Endo-dig rationale Alkyne has two π* orbitals-one in the plane of the ring

Disfavoured 3- and 4-exo-dig Nucleophile cannot attack at the required 120° angle

Exceptions to the Baldwin’s rules second row elements Why? Long C-S bond Sulfur has empty 3d orbitals cations

Summary Size Exo Endo Tet Trig Dig 3  X 4 5 6 7

Intramolecular endocyclic alkylation of ketone enolates Nomenclature enolexo or enolendo orientation of the enolate C-C bond exo-tet or exo-trig with respect to the C-Y terminus 6 to 7 Favoured 3 to 5 Disfavoured 3 to 7 Favoured Baldwin, Kruse, JACS Chem Commun. 1977, 233

Oxygen alkylation vs. Carbon alkylation (Compare with disfavoured 5-endo trig) (Compare with favoured 6-endo-trig)

Oxygen alkylation vs. Carbon alkylation Oxygen alkylation -electrophile approaches in plane of the enolate Carbon alkylation in 6-enolendo possible Perpendicular approach to the enolate

Intramolecular aldol condensations Favoured 3 to 7 disfavoured 3 to 5 favoured 6 to 7 Baldwin, Tetrahedron, 1982, 38, 2939

5-enolendo-exo-trig vs. 6-enolendo exo-trig 6-enolendo-exo-trig exclusively formed.

Summary Exo-Tet Exo-Trig Size enolendo enolexo 3 X  4 5 6 7

1. Exo-tet and endo-trig favoured 2. 5-endo trig disfavoured* Just remember..... 1. Exo-tet and endo-trig favoured 2. 5-endo trig disfavoured* 3. Endo-dig favoured 1. Enolexo endo-tet and trig are favoured Endocyclic reactions

Other Than Nucleophilic Cases Radical Processes (homolitic): Cationic Processes: