Trends in Acidity Lab

This lab is a guest post from Jay Sahni.

Overview

This lab introduces the basic trends in acidity for predicting relative acidity of different molecules. This lab is designed for an introductory organic chemistry course, and expects firm understanding of organic chemistry nomenclature, functional groups, and equilibrium.

What Even is Acidity?

While there are three major theories that describe acids and bases, Brønsted–Lowry acid–base theory is most relevant when discussing the acids in this lab. In Brønsted-Lowry acid–base theory, an acid is defined as a donor of an H⁺ ion (a proton) while bases are defined as acceptors of an H⁺ ion.

Lets consider acetic acid in water:

CH₃COOH(aq) + H₂O(l) ⇌ CH₃COO^–(aq) + H₃O⁺(aq)

In this reaction, acetic acid acts as our Brønsted–Lowry acid while H₂O acts as our base. Notably, the reverse reaction is also an acid–base reaction that's in equilibrium with the forward reaction:

CH₃COOH(aq) + H₂O(l) ⇌ CH₃COO^–(aq) + H₃O⁺(aq)

In this example, the acetate anion acts as a base while H₃O⁺ acts as an acid. We call H₃O⁺ the conjugate acid of H₂O and acetate the conjugate base of acetic acid.

In order to quantitatively assess the "acidity" of a species, we use the equilibrium constant (K_eq) of an acid's reaction with H₂O. Since water has ≈55 moles/liter (at STP), any changes in the concentration of water are negligible when dealing with dilute solutions (e.g. < 1 molar), and it can thus be treated as a constant and absorbed into our K_eq. This new value is called the K_a, or the acid dissociation constant.

K_a = [H₃O⁺][A^–] / [HA]

HA and A^– represent our acid and its conjugate base, respectively.

While we could stop here and use K_a to quantify aqueous acidity, K_a values of different molecules can range from over 1,000 to less than 10^–40! To avoid dealing with massive ranges in magnitudes, chemists created pK_a: a negative log scale of K_a.

pK_a = –log₁₀(K_a)

Molecules are more acidic if they readily react with water to form their conjugate bases, and thus have low pK_a values. Conversely, mildly acidic species have higher pK_a values as they do not readily form their conjugate base in the presence of water.

Let's examine a basic comparison to illustrate this: acetic acid vs. ethanol.

As you can see from the calculations below, acetic acid's pK_a is predicted to be over 10 units lower than ethanol. Undoing the logarithm, acetic acid is shown to be over 10¹⁰ times more acidic than ethanol.

Acetic Acid

Ethanol

Trend Predictions

While it's easy to memorize a trend, it's a lot harder to predict them based on theory. Answer the questions below to the best of your ability, and use them to guide your simulations in the next part.

Compare a generic alcohol (−OH) and a generic thiol (−SH). What is significantly different between Oxygen and Sulfur? Which would have the most stable conjugate base? How would this affect K_a?

What about a primary amine (R−NH₂) vs a generic alcohol? What is different between the two and how would that influence their acidity?

Now think about a carboxylic acid (R−COOH) compared to our original alcohol? What is special about the conjugate base of a carboxylic acid vs. an alcohol?

Finally, how does adding fluorine groups to a carbon chain affect its electron density? If we add fluorine groups to an alcohol, how would that change the charge dispersion of its conjugate base? Would that increase or decrease its stability?

Computational Investigation

Now, lets use computation to help us understand the trends in pK_a for 5 similar acids with a propane base structure: 1-propanol, 1-propanethiol, 1-aminopropane, propanoic acid, and 3,3,3-trifluoro-1-propanol. Guess the pK_a for each of the molecule, and then calculate the pK_a of the molecules using the directions below. Did you predict the correct trends in acidity?

Getting Started

1. Login to Rowan, create a new project called "Labs" (if not already created), and enter the project.
2. Create a new folder called "Trends in Acidity" (click on folder button in left panel), and enter the folder.

Micro pK_a Calculation

1. Click on the Microscopic pK_a prediction button.
2. Click on Draw 2D, draw the target molecule, and click Save.
3. The input menu will be highlighted in yellow. Change the name of the molecule and then click on the cube icon to convert the 2D structure to 3D.
4. Click Submit Micro pK_a.

Self-Exploration

It's your turn now! Think of other functionalizations that can be made to propanol. Test how multiple different functional groups affect acidity of our base propanol, or try creating complex structures and seeing how the pK_a changes for yourself. Write down a guess before running calculations and see if you can correctly predict the trends.

Note: multiple protonation sites may lead to incorrect predictions with the microscopic-pK_a workflow due to incorrect modeling of tautomers (for those interested, check out the discussion on microscopic and macroscopic-pK_a).

Challenge Question

You are tasked with reducing the acidity of propanoic acid (i.e. increasing the pK_a). Without removing any carbon or oxygen atoms from propanoic acid, discover two different ways you can make the molecule less acidic. Use Rowan to aid your discovery and to find the pK_a values of your two new molecules.

Which change (functionalization) achieves the greatest change in acidity, and why?

Review

1. How is acidity of an acid related to the stability of its conjugate base?

2. How does changing oxygen to sulfur affect the pK_a? Why might this occur?

3. How does changing oxygen to nitrogen affect the pK_a? Why might this occur?

4. Would the amino group be better or worse as a base than the alcohol? Why?

5. Compare the conjugate bases of 1-propanol and propanoic acid. What are the two major differences?

6. Why does the addition of the fluorine atoms significantly affect pK_a, even though they are far from the site of deprotonation?