Modeling Addition and Substitution Reactions

by Milca Pierre and Ari Wagen · Mar 20, 2025

This blog was written with friend of Rowan Milca Pierre. Milca is an undergraduate studying chemistry at the University of Massachusetts Lowell.

In this blog post, we'll be looking at an exercise from The Molecular Modeling Workbook for Organic Chemistry by Warren J. Hehre, Alan J. Shusterman, and Janet E. Nelson (Internet Archive, Amazon). Exercise 1 of chapter 13 looks at addition and substitution reactions, asking:

Unsaturated hydrocarbons undergo a variety of reactions. Experimentally, alkenes & alkynes undergo addition reactions whereas aromatic molecules, such as benzene, undergo substitution reactions instead. Why?

To answer this question, the workbook directs us to calculate the thermodynamics of each reaction. We'll be looking at two different sets of products (cyclohexane and benzene) and calculating the energy of the addition of bromine and corresponding substitution reaction for each.

Our goal is to determine which reactions are exothermic, which are endothermic, and by how much.

Figure 1: Addition and substitution reactions of cyclohexene and benzene with Br2

Figure 1: Addition and substitution reactions of cyclohexene and benzene with Br2

To quickly explore the thermodynamics of these reactions, we'll calculate the energy of each set of reactants and products using the AIMNet2 (ωB97M-D3) level of theory.

Cyclohexene + Br2

Here are the involved Rowan calculations:

Running these optimizations and plotting the thermodynamic change using Rowan's graph builder utility shows us that, although both the addition and substitution reactions are exothermic, the addition reaction is more exothermic. The addition reaction is, therefore, thermodynamically favored, accounting for the observation that "alkenes & alkynes undergo addition reactions."

Figure 2: Thermodynamics of the cyclohexene + Br2 addition and substitution reactions (transition states not modeled)

Figure 2: Thermodynamics of the cyclohexene + Br2 addition and substitution reactions (transition states not modeled)

Benzene + Br2

Here are the involved Rowan calculations:

The results of these calculations show that the addition reaction is endothermic, while the substitution reaction is exothermic. This means that the substitution reaction is thermodynamically favored, explaining the observation that "aromatic molecules, such as benzene, undergo substitution reactions."

Figure 3: Thermodynamics of the benzene + Br2 addition and substitution reactions (transition states not modeled)

Figure 3: Thermodynamics of the benzene + Br2 addition and substitution reactions (transition states not modeled)

To model these reactions' kinetics and predict which pathways would be kinetically favored, we would need to find and optimize each involved transition state. This would be a research project too large for a single blog post—these reactions are very solvent-dependent, may directly involve multiple solvent molecules or catalysts, and the transition-state structures are hard to find. We encourage the interested reader to see other sources looking at these reactions, including:

Figure 4: Computed transition-state structures of the benzene + Br2 substitution and addition reactions. Reproduced from figure 2 in Kong et. al (2011).

Figure 4: Computed transition-state structures of the benzene + Br2 substitution and addition reactions. Reproduced from figure 2 in Kong et. al (2011).

If you're interested in using Rowan to model your own reactions, you can do so through Rowan's web platform (it's free to make an account and get started). Happy computing!

Banner background image

What to Read Next

Using Implicit Solvent With Neural Network Potentials

Using Implicit Solvent With Neural Network Potentials

Modeling polar two-electron reactivity accurately with neural network potentials trained on gas-phase DFT.
Oct 7, 2025 · Corin Wagen
Preparing SMILES for Downstream Applications

Preparing SMILES for Downstream Applications

How to quickly use Rowan to predict the correct protomer and tautomer for a given SMILES.
Oct 3, 2025 · Corin Wagen
Better Search and Filtering

Better Search and Filtering

the problem of too many calculations; new ways to search, filter, and sort; how to access these tools; future directions
Sep 30, 2025 · Ari Wagen and Spencer Schneider
Boltz-2 Constraints, Implicit Solvent for NNPs, and More

Boltz-2 Constraints, Implicit Solvent for NNPs, and More

new terms of service; comparing IRCs and conformer searches; contact and pocket constraints for Boltz-2; MOL2 download; implicit-solvent NNPs; draft workflows; optimizing docking efficiency
Sep 22, 2025 · Corin Wagen, Ari Wagen, Jonathon Vandezande, Eli Mann, and Spencer Schneider
Controlling the Speed of Rowan's Docking

Controlling the Speed of Rowan's Docking

Some notes on how docking can be tuned for different applications.
Sep 22, 2025 · Corin Wagen
Studying Scaling in Electron-Affinity Predictions

Studying Scaling in Electron-Affinity Predictions

Testing low-cost computational methods to see if they get the expected scaling effects right.
Sep 10, 2025 · Corin Wagen
Open-Source Projects We Wish Existed

Open-Source Projects We Wish Existed

The lacunæ we've identified in computational chemistry and suggestions for future work.
Sep 9, 2025 · Corin Wagen, Jonathon Vandezande, Ari Wagen, and Eli Mann
How to Make a Great Open-Source Scientific Project

How to Make a Great Open-Source Scientific Project

Guidelines for building great open-source scientific-software projects.
Sep 9, 2025 · Jonathon Vandezande
ML Models for Aqueous Solubility, NNP-Predicted Redox Potentials, and More

ML Models for Aqueous Solubility, NNP-Predicted Redox Potentials, and More

the promise & peril of solubility prediction; our approach and models; pH-dependent solubility; testing NNPs for redox potentials; benchmarking opt. methods + NNPs; an FSM case study; intern farewell
Sep 5, 2025 · Eli Mann, Corin Wagen, and Ari Wagen
Machine-Learning Methods for pH-Dependent Aqueous-Solubility Prediction

Machine-Learning Methods for pH-Dependent Aqueous-Solubility Prediction

Prediction of aqueous solubility for unseen organic molecules remains an outstanding and important challenge in computational drug design.
Sep 5, 2025 · Elias L. Mann, Corin C. Wagen