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Substitution reactions can have really powerful effects, both good and bad, in our bodies. You might remember substitution reactions as displacement reactions from general chemistry, but (you guessed it!) in organic chemistry they’re a bit more complicated. In this episode of Crash Course Organic Chemistry, we’ll learn about the two pathways substitution reactions can take: SN1 and SN2 mechanisms, which substrates prefer which mechanism, and we’ll apply this knowledge by looking at how substitution reactions make chemotherapy treatments work.

Episode Sources:
Brookes, P., Lawley, P.D. “The Reaction of Mono-and Di-Functional Alkylating Agents with Nucleic Acids,” , Biochem. J., 1961, 80, 496-503.

Series Sources:
Brown, W. H., Iverson, B. L., Ansyln, E. V., Foote, C., Organic Chemistry; 8th ed.; Cengage Learning, Boston, 2018.
Bruice, P. Y., Organic Chemistry, 7th ed.; Pearson Education, Inc., United States, 2014.
Clayden, J., Greeves, N., Warren., S., Organic Chemistry, 2nd ed.; Oxford University Press, New York, 2012.
Jones Jr., M.; Fleming, S. A., Organic Chemistry, 5th ed.; W. W. Norton & Company, New York, 2014.
Klein., D., Organic Chemistry; 1st ed.; John Wiley & Sons, United States, 2012.
Louden M., Organic Chemistry; 5th ed.; Roberts and Company Publishers, Colorado, 2009.
McMurry, J., Organic Chemistry, 9th ed.; Cengage Learning, Boston, 2016.
Smith, J. G., Organic chemistry; 6th ed.; McGraw-Hill Education, New York, 2020.
Wade., L. G., Organic Chemistry; 8th ed.; Pearson Education, Inc., United States, 2013.

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Hi! I’m Deboki Chakravarti and welcome to Crash Course Organic Chemistry!

World War I has been called the "Chemist's War" because of chemical warfare agents such as phosgene, lewisite, and mustard gas. As bad reputations go, this was pretty horrific. After World War I, a paper published in 1931 described an unexpected benefit of sulfur mustard: anti-carcinogenic, or cancer stopping, effects.

Fighting fire with fire, or cancer with mustard gas, would be way too dangerous for patients. So chemists went back to their lab benches. They found that by replacing the sulfur in mustard gas with a nitrogen, they were able to treat cancer and reduce some of the toxic side-effects in humans.

This new class of compounds were called the nitrogen mustards. And in 1946, nitrogen mustards were used to treat Hodgkin's lymphoma and chronic lymphocytic leukemia. By the 1950’s, another derivative of mustard gas called chlorambucil was marketed as a chemotherapy drug patients could take by mouth.

Nowadays, we understand that mustard gas, and the chemotherapy drugs inspired by it, cross-link DNA and keep it from replicating. Being able to stop cancer cell DNA from replicating is hugely important in chemotherapy treatments. By the end of this episode, we’ll be able to see how substitution reactions make these chemotherapy agents work. [Theme Music].

We've learned that lots of addition reactions with alkenes or alkynes happen because pi bonds are nucleophilic. We added water, halogens, or other groups across a double or triple bond without removing any atoms. Alkanes don’t have electron rich areas, so in episode 19, we used radical reactions to turn them into alkyl halides.

These reactions gave us a way to halogenate alkanes, basically installing molecular hotspots. 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 just has to… 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: An sp3 hybridized carbon, which we’re going to call the substrate. Number 2: A leaving group, which is an atom or group that can accept electron density. And Number 3: A nucleophile, which is an atom or group that contains a lone pair or a pi bond.

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.

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 SN1 and SN2. 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 SN1. 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 SN1 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, the rate-determining step is also called the slow step. And the reason we call SN1 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 SN1 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 doesn’t determine the overall rate. Those are the basic steps along the SN1 pathway. But it's one thing to watch a complicated dance or imagine a merry-go-round, and another thing entirely to use your muscles.

So let's go through a specific reaction mechanism in detail. We'll react 2-methyl-2-bromopropane, more commonly known as tert-butylbromide, with water. First, we have the formation of the carbocation, our slow, rate-determining step where bromine leaves.

And next, we have the nucleophilic attack on the substrate, which is relatively fast: water attacks the carbocation, and we see our familiar “one-two punch” where a second water molecule scoops up the proton from the oxonium ion. If we plot this reaction on an energy diagram, we can see that the activation energy is really big for the dissociation of the bromide ion. It takes a lot of oomph for that slow step to get going!

On the other hand, the activation energies for the nucleophilic attack and the deprotonation reaction are relatively small. So these reactions happen pretty quickly in comparison. Now, we should also pay attention to the stereochemistry of these molecules.

During that first transition state when the bromide leaves and the carbocation forms, the molecule flattens out like a pancake. Overall, there's a trigonal planar molecular geometry: three methyl groups around an sp2 hybridized carbon with an empty p orbital. Our carbocation!

SN1 reactions prefer tertiary carbocations, which are stable thanks to those effects we talked about in episode 14: induction and hyperconjugation. We’ll get into more details about why this happens in the next episode! Anyway, a flat intermediate means that the incoming nucleophile can attack the lobes of our p-orbital from either the front side (where the bromine just left) or the back side (which is, well, the other one).

If the groups around the central carbon are all the same, like the three methyl groups in our previous example, this isn’t super important. Our final product looks the same no matter which side the water molecule attacks. But if our substrate is chiral, we need to pay close attention because two different stereoisomers can form.

A nucleophilic attack from the front side gives us the same configuration we started with. But if the nucleophile attacks the back side, the stereochemistry flips, or inverts. If we started with a single enantiomer of the substrate, we would now have a racemic mixture of our reaction product.

Now this is key: carbons that have three bonds to a carbon make tertiary carbocations and their substitution reactions happen via an SN1 mechanism. But, substrates that have one carbon substituent (called primary) or two carbon substituents (called secondary) usually take a completely different path: they follow an SN2 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 SN2 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. SN2 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. SN2 is a much rowdier playground than SN1! Once again, it's easy to make dance or playground analogies, and tricker to go through a specific reaction mechanism.

So let's look at what happens if we do a substitution reaction with (R)-2-iodobutane, a chiral substrate. Our nucleophile involves a sulfur atom, which attacks the substrate and kicks out our leaving group, the iodine, in one mighty swoop. And if we look at the energy diagram for this reaction, we can see how it's a concerted reaction: there's one big hill without any intermediates.

So even though SN1 and SN2 mechanisms have similar names, the pathways are pretty different when you look closely, especially at experimental evidence. For instance, when chemists experimentally tested reaction rates, they learned that SN1 only depends on the concentration of substrate and SN2 depends on both the substrate and the nucleophile. And we know that tertiary substrates work better for SN1 but they don’t do SN2 at all.

Nucleophiles can't squeeze in, do a backside attack, and force a whole inside-out umbrella flip on a super bulky tertiary substrate. The substrate has to lose its leaving group and flatten out first. All the details of substitution reactions can be tricky, so let's summarize everything we've learned about SN1 and SN2 mechanisms in a table, which we'll add to over the next few episodes.

And now, let's finish by looking at an important SN2 mechanism in medicine. We can apply everything we’ve learned about substitution reactions to the example we started with: . DNA and nitrogen mustard, or mechlorethamine.

The nucleophile and the leaving group are on the same molecule, but it's still a substitution reaction because it involves those three key things! First, we have an intramolecular SN2 reaction, where the nucleophilic nitrogen attacks by chlorine, the leaving group on the chain attached to the nitrogen. This forms a three-membered ring with the nitrogen, basically the nitrogen equivalent of the epoxide molecule we saw in episode 17.

Then, another nucleophile saunters in: the DNA molecule! The nitrogen on one of the nitrogenous bases of DNA does an SN2 reaction, attaching to nitrogen mustard, and opening up the strained three-membered ring. Finally, the whole process repeats with the paired strand of DNA, linking them together.

Thanks to these two substitution reactions, we have two DNA strands tangled up with our nitrogen mustard substrate. This is what I mean by crosslinking! It physically keeps these DNA strands from replicating, which means cell death… and that's the basis of many chemotherapy treatments.

In this episode, we learned that:. An SN1 mechanism occurs through a carbocation intermediate and the stereochemistry can be the same configuration or inverted. An SN2 mechanism occurs through a concerted process and the stereochemistry is always inverted.

Tertiary substrates favor SN1 mechanisms, while secondary and primary substrates favor SN2. And substitution reactions can be really powerful (good and bad) when it comes to DNA. Next time, we’ll get deeper into the reaction conditions that favor one substitution reaction mechanism over another and fill in more details in our table.

Until then, thanks for watching this episode of Crash Course Organic Chemistry. If you want to help keep all Crash Course free for everybody, forever, you can join our community on Patreon.