Baldwin's Rules

Baldwin's rules in organic chemistry are a series of guidelines outlining the relative favorabilities of ring closure reactions in alicyclic compounds. They were first proposed by Jack Baldwin in 1976.

Baldwin's rules discuss the relative rates of ring closures of these various types. These terms are not meant to describe the absolute probability that a reaction will or will not take place, rather they are used in a relative sense. A reaction that is disfavoured (slow) does not have a rate that is able to compete effectively with an alternative reaction that is favoured (fast). However, the disfavoured product may be observed, if no alternate reactions are more favoured.

The rules classify ring closures in three ways:

*the number of atoms in the newly formed ring
*into ''exo'' and ''endo'' ring closures, depending whether the bond broken during the ring closure is inside (''endo'') or outside (''exo'') the ring that is being formed
*into ''tet'', ''trig'' and ''dig'' geometry of the atom being attacked, depending on whether this electrophilic carbon is ''tet''rahedral ( sp³ hybridised), ''trig''onal ( sp² hybridised) or ''diag''onal ( sp hybridised).

Thus, a ring closure reaction could be classified as, for example, a 5-''exo-trig''.

Baldwin discovered that orbital overlap requirements for the formation of bonds favour only certain combinations of ring size and the ''exo/endo/dig/trig/tet'' parameters.

There are sometimes exceptions to Baldwin's rules. For example, cations often disobey Baldwin's rules, as do reactions in which a third-row atom is included in the ring. An expanded and revised version of the rules is available:

The rules apply when the nucleophile can attack the bond in question in an ideal angle. These angles are 180° (Walden inversion) for ''exo-tet'' reactions, 109° ( Bürgi–Dunitz angle) for ''exo-trig'' reaction and 120° for ''endo-dig'' reactions. Angles for nucleophilic attack on alkynes were reviewed and redefined recently. The "acute angle" of attack postulated by Baldwin was replaced with a trajectory similar to the Bürgi–Dunitz angle by Alabugin and coworkers. This change, fully consistent with the stereoelectronic rules for nucleophilic addition at a pi-bond, reversed Baldwin's predictions for alkyne cyclizations. The combined body of experimental and computational data, not available to Baldwin, strongly supports the notion that exo-cyclizations are more favorable than endo-cyclizations for both alkenes and alkynes.

Applications

In one study, seven-membered rings were constructed in a tandem 5-''exo-dig'' addition reaction / Claisen rearrangement:

:

A 6-''endo-dig'' pattern was observed in an allene - alkyne 1,2-addition / Nazarov cyclization tandem catalysed by a gold compound:

A 5-''endo-dig'' ring closing reaction was part of a synthesis of (+)-Preussin:

:

Rules for enolates

Baldwin's rules also apply to aldol cyclizations involving enolates. Two new descriptors need to be defined: ''enolendo'' and ''enolexo'', which refer to whether both carbons of the enolate C-C fragment are incorporated into the ring formed or not, respectively.

:

The rules are the following:

Exceptions

These rules are based on empirical evidence and numerous "exceptions" are known.Finding the right path: Baldwin "Rules for Ring Closure" and stereoelectronic control of cyclizations. Alabugin, I. V.; Gilmore, K. Chem. Commun., 2013, 49, 11246 – 11250. http://pubs.rsc.org/en/content/articlehtml/2013/cc/c3cc43872d Examples include:
* cyclisations of cations
* reactions involving third-row atoms, such as sulfur
* Transition metal catalysis

References

{{Reflist, 2

Eponymous chemical rules
Physical organic chemistry
Stereochemistry