Studying Racemization Using DFT and Identity Reactions

In this section, I’ll walk you through how I use Density Functional Theory (DFT) and the concept of identity reactions to computationally understand racemization. The data is based on the published paper titled “Sulfur–Phenolate Exchange: SuFEx-Derived Dynamic Covalent Reactions and Degradation of SuFEx Polymers”.

We’ll compare the activation barriers of a desired stereospecific reaction (SuPhenEx) against a competing, undesired pathway (an identity reaction) that leads to racemization, resulting in loss of enantiospecificity (es) in some of the phenolates with electron-withdrawing groups (EWGs).

Step 1: SuPhenEx Activation Barriers (ΔH‡)

The table below shows the calculated activation enthalpies (ΔH‡) for SuPhenEx reactions with different substituents:

Substituent (R)                       ΔH‡ [kcal/mol]
p-OMe                       9.6
p-H                       11.6
p-CN                       19.3

As the substituent becomes more electron-withdrawing, the ΔH‡ increases, indicating that the SuPhenEx reaction becomes slower.

Step 2: Identity Reaction (Racemization Pathway)

To understand how racemization occurs, I model identity reactions, where a product molecule exchanges phenolates with itself. This results in stereochemical scrambling without any net change in structure.

How I Set Up Identity Reactions in DFT:

  1. Use the product structure (e.g., para-Nitro-phenolate) as the starting geometry.
  2. Construct a symmetric transition state, where the leaving and entering phenolates are equidistant. Refer image Racemization TS
  3. Adjust bond distances and angles to create a mirror-symmetric geometry.
  4. Optimize using a suitable DFT method (e.g., B3LYP-D3(BJ)/def2-TZVP) with solvation if needed.

Here are the calculated activation barriers for identity reactions:

Substituent (R)                       ΔH‡ [kcal/mol]
p-OMe                       19.3
p-H                       19.4
p-CN                       20.9
p-NO₂                       22.4

These ΔH‡ values are consistently higher than those for SuPhenEx, but the gap narrows with EWGs.

Step 3: Interpreting ΔΔH‡ — The Selectivity Indicator

To assess how likely racemization is, I compute:

ΔΔH‡ = ΔH‡(identity) − ΔH‡(SuPhenEx)

Substituent (R)                       ΔΔH‡ [kcal/mol]
p-OMe                       9.7
p-H                       7.8
p-CN                       1.6

Low ΔΔH‡ values (e.g., p-CN i.e., (S)-3k) imply that the racemization pathway is energetically competitive with SuPhenEx, explaining why enantiospecificity breaks down in these cases. This also suggests starting with a leaving group containing p-NO₂ is useful in avoiding the racemization as the identity reaction barrier for p-NO₂ is the highest among the substituents.

Summary

  • DFT allows me to quantify racemization potential by comparing the ΔH‡ of SuPhenEx and identity pathways.
  • Symmetrizing the product is essential to locating the racemization transition state.
  • ΔΔH‡ gives a clear metric for stereochemical robustness.

This computational approach helps explain experimental results and serves as a predictive guide for designing more robust enantiospecific reactions.