Viva Survivor: Baldwin's rules

This is the first of the basic science posts we will be running about once a week; first up is Baldwin's rules (or guidelines as many prefer), for more detail look here. 

Baldwin’s rules are empirical observations of possible cyclisation reactions, classified according to the size of the ring being formed, the nature of the electrophilic portion of the molecule and whether the bonds are broken inside or outside of the ring.  Although the based on empirical observation they use stereochemical reasoning including orbital overlap and the preferred angle of attack of a nucleophile. Because they are essentially empirical they are not really rules in the Woodwood—Hoffman sense of the word, but should be thought of as guidelines; there are exceptions!

Reaction classification

•  The ring being formed has three members, the C-Br bond is outside the ring the carbon being attacked is sp³: so the reaction is a 3-exo-tet cylisation which is favoured.

• This time the ring being formed has 5 members again the breaking C=O bond is outside the ring, but the electrophilic carbon is sp² hybridised: so the reaction is a 5-exo-trig cyclisation which is favoured.

• Finally, in this case the ring formed will be 6 membered, the carbon-carbon bond is broken inside the ring and the electrophilic carbon is sp hybridised: so the reaction is a 6-endo-dig cyclisation which is favoured.

    

     Use in understanding reaction mechanisms

     Exo-tet cyclisations and exo-trig cyclisations have no stereochemical issues and will always be able to achieve orbital overlap necessary to carry out the reaction.

     Obviously this is not true for all cyclisation or there would be no rules! For example, Eschenmoser was able to disprove this superficially acceptable mechanism (below) because poor orbital overlap would not allow the intra-molecular process to occur. Analysis of both mechanisms using Baldwin's rules shows that the intra-mechanism is disfavoured whereas the inter molecular process is favoured.

     The most important example of a class of cyclisations that looks fine on paper, but usually does not work in practice, is the 5-endo-trig cyclisation. The reason they don’t work is that it is difficult to get good orbital overlap (below).

     Baldwin’s rules also work just as well for ring opening reactions and the rules apply in the same way. This explains the following reaction which looks (on paper) to be set up to do the E1cb reaction, but it is not possible due to poor orbital overlap. 

     Exceptions to the rules

     As mentioned earlier there are many exceptions to the “rules”, some of these are very well known, larger atoms such as Sulfur are able to use their empty d-orbitals to be able to interact with the π orbital. Similarly cations are frequently able to break the rules in cases where a there is a powerful thermodynamic driving force to drive the reaction; this is an important point: because Baldwin’s rules describe orbital overlap they describe the kinetic forces that drive reactions. Examples of these exceptions are shown below.  

   Summary Endo cyclisations

TET (sp3)	3	4	5	6	7
TRIG (sp2)	3	4	5	6	7
DIG (sp)	3	4	5	6	7

   In general: endo-tet and endo-trig cyclisations are DISFAVOURED 

   In general: Endo-dig cyclisations are FAVOURED

   Summary Exo cyclisations

TET (sp3)	3	4	5	6	7
TRIG (sp2)	3	4	5	6	7
DIG (sp)	3	4	5	6	7

   In general: Exo-tet and Exo-trig cyclisations are FAVOURED 

   In general: Exo-dig cyclisations for smaller ring sizes are DISFAVOURED