Cram's Rule - Open Chain Model

Cram's Rule - Open Chain Model

Cram’s Rule is a stereochemical model used to predict the major product in nucleophilic additions to carbonyl compounds, especially when the carbonyl carbon is adjacent to a chiral center. Two key models for applying Cram’s Rule are the open-chain model and the cyclic model.

Open-Chain Model

1. Description:

   • Assumes a staggered conformation of the molecule.
   • The three substituents on the adjacent chiral center (R, M, S) adopt specific positions relative to the carbonyl group.

2. Orientation:

   • The largest substituent (L, usually R) adopts the anti-periplanar position relative to the carbonyl group to minimize steric hindrance.
   • The nucleophile approaches from the less hindered side of the carbonyl, opposite the medium-sized substituent (M).

3. Predictive Power:

   • Works well for simple open-chain aldehydes and ketones.
   • Predicts the major diastereomer based on steric interactions in the staggered conformation.

4. Limitations:

   • Does not account for potential electronic effects or intramolecular interactions that may override steric factors.
   • Struggles with accuracy in cases where conformational flexibility alters the expected geometry.

For example, suppose we have the following aldehyde.  The asymmetric center has three groups other than the formyl group - a big group (Ph), a medium group (CH₃) and a small group (H).  The most stable conformation of the aldehyde is such the carbonyl rests between the medium and small groups as follows. The attacking nucleophile would prefer to attack from the side of the small group, resulting in the predominant formation of one diastereomer in the product.

For example addition of phenyl magnesium bromide to the above aldehyde results in the following.