Hi! I’m Deboki Chakravarti and welcome toCrash Course Organic Chemistry! Have you ever played an adventure game? The sort of thing where you start with a character,get some equipment, and go on a quest? We can imagine organic chemicals as thesekinds of characters! Our adventuring protagonist is our substrate. Different substrates can be sorted into classes,which can undergo different transformations. Specifically, our heroes can take on incrediblenew forms through the substitution and elimination reactions we’ve been learning for the pastfew episodes.
In this episode, we’ll learn how to beatthis adventure game: how to take any substrate, combined with anynucleophile, and predict what kind of new adventurer thetransformation will produce! [Theme Music] First of all, let’s set up our “world”to reveal the rules that our substitution and elimination reactions must follow. In terms of starting characters, we have afew fundamental classes: methyl, primary, secondary, and tertiary substrates. Our substrate is always an sp3 hybridizedcarbon, and the classes refer to how many.
Carbon substituents they have. Primary is one, secondary is two, and tertiaryis three. So a tertiary substrate is our bulkiest characteroption. Our substrates encounter different nucleophiles,which change the substrate through a chemical reaction. We can think of nucleophiles as differentmagic potions. Some are stronger, some are weaker, and thetransformative potion effects depend on what the substrate is, and the surrounding reaction conditions. In our world, if a character is in a desertkingdom, a potion could work differently than it would on a character in an icy cavern!.
And there are four major transformations inthis world — types of substitution and elimination reactions. If you need more of a refresher, rewatch episodes20 through 22! In both SN1 and E1 mechanisms, a carbocationintermediate forms. In the SN1 substitution reaction, the nucleophilecan attack the carbocation from either side, so we get a mixture of stereoisomers at achiral carbon. And in the E1 elimination reaction, the nucleophileacts as a base, deprotonating the substrate, and we get an alkene. On the other hand, both SN2 and E2 mechanismshappen in one, single step.
In the SN2 substitution reaction, the nucleophile's backside attack on the substrate inverts the stereochemistry at a chiral carbon. And in the E2 elimination reaction, we needan antiperiplanar leaving group and beta hydrogen for the nucleophile to deprotonate the substrate,creating an alkene. Okay! Let’s look at how different potions—ornucleophiles— transform our characters—or substrates. We’ll start with the smallest characterclass: methyls. Since they only have one carbon, there areno beta hydrogens, so they can't do an E2 transformation.
They also can’t form stable carbocations,which means they're resistant to any SN1 and E1 reactions. That leaves us with one option: methyl substrates only do SN2 reactions, nomatter what nucleophile they encounter. And, in fact, with poor nucleophiles, methylsubstrates either don’t do anything, or react so slowly that it’s just not worth it. I mean, come on, we need to take our potionand get on with this adventure! Let’s take a look at a specific methyl substrate,bromomethane, and its reactions with three different nucleophiles. In each case, our starting character is transformedby an SN2 reaction.
There’s only one carbon, so there’s onlyone place each nucleophile can go, and one option for our character's final form, the reaction product. Easy! Next, let's look at primary substrates. These characters have more carbons than methylsubstrates, but the leaving group is at the end of thechain. So primary substrates also don't form verystable carbocations, which rules out SN1 and E1 reactions.
And if they encounter a poor nucleophile,not much will happen. Mostly, we see SN2 substitution reactions. For example, there's the Williamson etherification,named after its discoverer, English chemist Alexander William Williamson. Our character here is a primary alkyl halide,and our potion is a strongly nucleophilic alkoxide. After an SN2 transformation, our hero becomesan ether! But primary substrates can also undergo E2elimination reactions when there's a certain type of potion… or, nucleophile. Specifically, when primary substrates encountera strong, bulky base.
Steric hindrance makes it tricky for the bigbase to displace the leaving group with a backside attack, so it just grabs one of thebeta hydrogens and runs. That's elimination, not substitution! Now, primary substrates also have some specialsubclasses: primary allylic and primary benzylic substrates. These substrates have double bonds or benzenerings that stabilize carbocations by resonance. Also, polar, protic conditions “slow down”the effects of our nucleophile potions, so the nucleophile doesn’t attack immediately,there's time for a carbocation to form, and we’ll get SN1 reactions.
For example, here's a reaction with a primarybenzylic substrate that forms an ether. We can see that hydrobromic acid is a product,which is another hint that we have an SN1 reaction. Remember from episode 21: “when we see acid as a reactant or product,think SN1.” If we increase the strength of our nucleophile, or switch from a more sluggish polar, protic environment to an aprotic one, these special substrates act like other primary substrates and favor SN2 reactions. Time for some secondary characters — andno, I don't mean sidekicks! Secondary substrates include some of the mostimportant potions and reaction conditions to learn, because they have the most competing mechanisms.
Secondary substrates have all the traits ofless bulky character classes that allow for SN2 and E2 reactions. But they also have some branching, which meansmore stable carbocations, and that SN1 and E1 reactions are possibletoo. To start, let's look at an SN1 transformation example, with a secondary substrate and acetic acid as our nucleophile — that hint from episode 21 about acids andSN1 applies again! And these are polar, protic conditions thatslow down our nucleophiles and give carbocations time to form. In SN1 reactions, the nucleophile can attackeither face of the carbocation. So if our substrate has a chiral carbon (andin this case, it has two) the stereochemistry gets scrambled.
Here, we get a mixture of diastereomers asproducts. Remember from episode 9, these can occur whena compound has more than one chiral center and, as a result, has stereoisomers that aren'tmirror images of each other. The non-reacting chiral center from the startingmaterial keeps its configuration in both products, but the reacting chiral center ends up R inone diastereomer, and S in the other. But here's why we have to be so careful: when our secondary character drinks this potion,we're not guaranteed an SN1 transformation. Substitution and elimination can compete! Once a carbocation forms, the nucleophilecan deprotonate our substrate,.
So some E1 products get formed too. Now, let's look at an SN2 transformation,with a tosylated alcohol as our substrate and a weakly basic nucleophile. DMSO as a solvent gives us polar aprotic conditions,which tend to give the nucleophile a bit of a boost! In other words, polar, aprotic conditionsstrengthen our potions, so even a weak nucleophile can attack oursubstrate, favoring an SN2 reaction and inverted stereochemistry in the product. Now, if a secondary substrate encounters astrongly basic nucleophile, we tend to see E2 reactions.
Like I said, lots of competing mechanismswith this character class! Stronger bases are very reactive and quicklysteal a beta hydrogen — so long as it’s antiperiplanar to the leavinggroup, of course! This Newman projection reminds us why we getthe E-alkene as our final form — it has to do with the antiperiplanar hydrogenand leaving group rotating around the carbon-carbon bond. Pop back to episode 22 if you need a refresher. This example shows another way that the surroundingreaction conditions affect how our nucleophile potions work. Notice this reaction was heated — maybe thispart of the game is in a desert? And heat favors elimination reactions.
To understand why this is true, we have toremember our Gibbs Free Energy equation from episode 15: ΔG = ΔH − TΔS Increasing the temperature makes the entropyfactor more significant, which means we end up with a more negative delta G. So, with higher heat, a reaction that increasesentropy is more likely to happen spontaneously. Elimination reactions create more entropy than substitution reactions because they give us a greater number of products. We get a whole extra molecule by comparison,because the base runs off with a beta hydrogen. Now it's time for tertiary substrates — ourfinal class of characters! With all their branches, tertiary substratesare really good at forming stable carbocations.
So SN1 and E1 reactions are possible withweak nucleophiles. Being the bulkiest character class means thattertiary substrates have a lot of steric hindrance too, and can't undergo SN2 reactions. Nucleophiles can’t get close enough to attackthe electrophilic carbon from behind, so our only all-at-once reaction choice isE2 elimination. Substitution and elimination reactions compete, so we have to pay close attention to the nucleophilesthat favor one transformation over the other. For example, here are some tertiary substratesand two different reactants: hydrobromic acid or water.
Bromide and water are good nucleophiles, butpoor bases — so they're not so great at grabbing protons. That means they favor substitution over elimination,and our only substitution option is SN1. To encourage elimination over substitution,we can pick a different reactant: sulfuric acid, which forms the conjugate basebisulfate anion when it loses a proton. Remember from episode 22, a bisulfate ionis a poor nucleophile but it can act as a base. That means it's better at grabbing a proton,and E1 elimination is favored with our tertiary, and benzylic substrate. Now, let’s check out an example of an E2elimination reaction.
The key here is the strong base, which usuallygives us E2… When tertiary or secondary substrates transformthrough elimination, usually the major product that forms is the most substituted alkene. That's Zaitsev’s rule, which can be reallyhelpful when predicting our characters' final forms. In fact, we can see it in action here witha tertiary substrate and a sodium ethoxide potion. However, Zaitsev's rule has an exception witha special type of potion: a nucleophile that's a very bulky base. For example, the bulk of sodium tert-butoxidegets in the way. To form the Zaitsev product, this nucleophilewould need to grab a proton from a beta carbon.
But as the oxygen from the tert-butoxide iongets closer, there's a steric clash causing lots of repulsion,which slows the reaction down. Instead, the tert-butoxide ion just grabsthe proton from our less substituted beta carbon, reducing the clash, speeding up the reaction,and forming the less-substituted, non-Zaitsev product. Substitution and elimination reactions canbe really tough. Trust me, I've been there. So here's a table to organize what we've learned. Remember that it'll take more than memorizationto solve these puzzles:.
Really imagine our game world, the substrate characters, and how the nucleophile potions might transform them. And, of course, practice helps. So it's time for some rapid fire problems! We’re going to put four problems on screenthat could be SN1, SN2, E1 or E2 and predict the likely mechanism and the products. Then, we'll work through the answers, so pauseright after the question if you want to solve them yourself. Player 1, are you ready to start this game? Here's problem number one.
We have a secondary benzylic substrate withmethanethiol as our nucleophile. Looking at the table, negatively charged sulfurgroups are weak bases, so we might expect SN2, but here we have athiol, and since the sulfur is protonated, an “S-H” group, we have acidic or neutral conditions. Using our handy hint, remember acidic conditionsfavor SN1! Because we have a chiral center, we also geta mixture of enantiomers. And don't forget that pesky minor productby E1. Here's problem number two.
This time the substrate is secondary again,but the nucleophile is an acetylide anion. Acetylide anions are strong nucleophiles andsuper strong bases, which means this reaction strongly favorselimination — specifically E2. And there’s a mixture of products. Following Zaitsev’s rule, we would expectbut-2-ene as the major product since it’s more substituted. Then, looking at that major product, we expectmore trans than cis, because that’s the form where we get themost energetically stable arrangement — when the methyl groups are spaced as far apartas possible. Here's problem number three.
We have another secondary substrate with methanol,a poor nucleophile. We also have polar, protic conditions. Looking at our reactants, we expect to seeHBr as a product, which is acidic — so using that handy hint, we think we're dealingwith SN1. But there’s something else to consider. The intermediate is a secondary carbocationwhich is less stable than a tertiary carbocation. And if a less stable carbocation can get morestable through the migration of a C-H bond, then a rearrangement can occur. We've got to look out for these tricks!.
This migration is called a hydride shift. So we actually end up with a tertiary carbocation,and this substitution product. And lastly, here's problem number four. Here we have one more secondary substrate,and sodium acetate, which is a weak nucleophile. This is a nice simple setup, and it reactseasily by the SN2 mechanism. That’s it for this episode! Next time, we’re going to be looking moreat alcohols, ethers and epoxides. Until then, thanks for watching this episodeof Crash Course Organic Chemistry. If you want to help keep all Crash Coursefree for everybody, forever,.
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