A Journey into Substitution Reactions by Crash Course

Note from Chemistry Hall: Today I would like to share with you a recommendation of a YouTube channel. This is how the people at ‘Crash Course’ tackle organic chemistry teaching by using videos. I checked a couple of videos and they explain important concepts in a clear and conversational manner. If you are learning organic chemistry at an introductory level, be sure to check it out! Now follows the guest presentation by the editors of the course:

For many students, video content is a useful tool to supplement classroom learning and review concepts. At Crash Course, we create free online video courses on Youtube focused on a wide variety of subjects, from literature to chemistry. Over the past few months we have been making a new series of videos that are being uploaded weekly. Here you can find the presentation video and the YouTube channel:

The first part of the series is focused on the tools that help us understand organic chemistry, things like bonding, structure, and naming molecules. Once we have a basic toolbox, we start building molecules: from small molecules like ethanol to giant macromolecules like high-density polyethylene. In the second half of the course, we will get into multi-step synthesis of larger molecules. We’ll also look at important developments in the pharmaceutical industry because understanding organic chemistry is important in understanding health, medicine, and how the biochemistry of the body works. 

If this course sounds like a useful tool for your classroom or learning, you may also want to check out the Crash Course App (Google Play link here)! The app offers flashcards with review questions for each video in the organic chemistry series. 

If you’re interested in learning more about how a course like this is built and written, below is a message from the Content Manager of Crash Course, Ceri Riley, as well as a script excerpt.

A Presentation by the Content Manager of Crash Course

When I took Organic Chemistry in college, it was incredibly tricky to wrap my brain around substitution reactions. I relied heavily on memorization, and even then, when it came time to solve problems, I felt like I was guessing when it came to SN1 and SN2 mechanisms. I’m really glad our expert consultant, Dr. Kristen Procko, decided to break substitution reactions into two episodes. And in this introductory episode, there are a few helpful logical breakdowns of the differences between SN1 and SN2, from using general models, to playground metaphors, and specific examples. 

Sharing CC Organic Chemistry scripts feels definitely like sharing a rough draft, because Deboki Chakravarti’s performance as host and Thought Cafe’s animations add SO MUCH to this series. It’s one thing to see a reaction mechanism in a textbook or in a script, and it’s another to see it fully animated. That being said, it takes a team of experts to get all these small details right: we have a consultant, writer, and fact checker. This is one of the biggest content teams we’ve ever had, and it’s partially because there are so many tiny things to get right, from subscripts to spelling to making sure our logic is clear and we’re giving as many tips as possible to help students with this difficult material. 

Hopefully this excerpt sheds some light into our scripting process and gives a sneak peak at some reactions we’re going to learn in a few months on the channel. I’m really proud of how much we packed into this episode (and honestly, all of these episodes) and hope they help many people in the upcoming months and years! 

– Ceri Riley, script editor of CC Orgo and content manager of Crash Course

Script Excerpt of CCORG20: Intro to Substitution Reactions

In general chemistry, you might’ve heard substitution reactions called displacement reactions. Like two pairs of dance partners, two ionic compounds in water could swap ions when mixed, so the positive part of one compound ended up with the negative of the other. 

In organic chemistry, substitution reactions also involve switching partners, but they’re a little more complicated. We usually deal with single displacement reactions, where one group finds a new partner and the other has to… just… leave. And organic molecules are a bit more complicated than inorganic ions, so we’ll have to think carefully about stereochemistry. 

Don’t worry though. We got this. To help us figure out organic substitution reactions, we need three things:

Number 1:  A molecule containing an sp³-hybridized carbon, which we’re going to call the substrate. This sp³-hybridized carbon will have a leaving group attached to it.

Number 2:  That leaving group, which is an atom or group that can accept electron density, and stabilize the negative charge that will hold after “leaving” the substrate.

And Number 3:  A nucleophile, which is an atom or functional group that contains a lone pair or a pi bond, and is electron-rich by nature.

This is the general model of a substitution reaction, with placeholders. 

We can add in some real atoms and molecules here: the substrate is 1-bromobutane, which switches its bromide dance partner for hydroxide. In this reaction, the leaving group is a bromide ion, and the nucleophile is a hydroxide ion.

The Mechanisms of Substitution Reactions

As we’ve been discovering, organic chemistry is full of puzzles, so substitution reaction mechanisms can get a little tricky. Specifically, they can take two paths called S_N1 and S_N2. Depending on the path, we’ll see differences in stereochemistry and mechanism. 

Let’s adventure along one pathway, or one mechanism, at a time. And we’ll start with S_N1. The S is for substitution, the N is for nucleophilic, and the 1 is for unimolecular, which tells us about the reaction rate. 

There are two steps to an S_N1 reaction: formation of a carbocation and nucleophilic attack. To see what this looks like in a reaction mechanism, let’s use a general model again.

First, formation of the carbocation is the rate-determining step. We’ve got to wait for that  leaving group to pop off of the molecule with its electrons and give the carbon a positive charge. 

Since this could take awhile, we say this first process is the rate-determining step, or the slow step of the entire reaction. And the reason we call S_N1 reactions unimolecular is because the overall rate of this reaction depends on that one molecule, the substrate, losing its leaving group.

Okay, I know we can broadly visualize substitutions as dancing, but I like to picture the details with a playground. Specifically, a merry-go-round — you know, those spinny platforms where you sit and someone else pushes it in circles until you’re super dizzy? Suppose there was a merry-go-round that could only hold three kids. You’re the fourth, so you get stuck spinning your friends, waiting for one to get off so you can hop on. It always feels like forever before you get a turn. But that’s basically the first step of an S_N1 reaction.

Now, a carbocation is pretty irresistible to nucleophiles, so next the nucleophile attacks this intermediate and a bond is formed. Sort of like how you’d quickly jump onto a merry-go-round to take a turn when your friend finally hops off. Because it happens so quickly, this step does not determine the overall rate.

Moving on to S_N2 Reactions

Those were the basic steps along the S_N1 pathway… But in an S_N2 mechanism, the S is for substitution, the N is for nucleophilic, and the 2 is for bimolecular – because the reaction rate will depend on two molecules coming together, instead of one just falling apart. Our two molecules are the substrate and the nucleophile. 

In an S_N2 mechanism, there is no carbocation intermediate and the nucleophile plays a much more active role. It all happens in one big, dramatic swoop: the nucleophile does a backside attack, pushes out the leaving group, and the stereochemistry gets inverted….kind of like an umbrella that gets turned inside-out in a heavy wind storm.  

Specifically, it’s another one of those funky concerted reactions where bonds break and form at the same time. S_N2 mechanisms go through a stage that looks like a carbon with five bonds. But it’s not, because both the nucleophile and leaving group are attached with partial bonds. 

A partial bond means as one bond is forming, the other is breaking. Basically, the nucleophile starts to share its electrons but doesn’t want to fully commit until the leaving group leaves. And the substrate doesn’t want to fully let go of the leaving group until the nucleophile commits. Kind of like a passionate ballet with dancers joining hands or letting go. 

Or, going back to our merry-go-round metaphor, it’s like you’re spinning three friends again. But instead of waiting patiently for one of them to hop off, you push one friend away and sit down across from where they were. Then your other friends, to balance it out (or just to get away from you) shift over. S_N2 is a much rowdier playground than S_N1!