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  • Hi!

  • I'm Deboki Chakravarti and welcome to Crash Course Organic Chemistry!

  • And to my home.

  • Where we're filming now because of the pandemic.

  • When your fancy clothes say "DRY CLEAN ONLY," maybe you justnever wash them.

  • When I was little, I thought dry cleaners dusted laundry detergent on clothes and then just ran them through a machine to get rid of the powder.

  • Dry cleaning isn't actually dry though, it's just using a liquid other than water to wash dirt away.

  • The most common liquid is tetrachloroethylene, also called perchloroethylene or perc for short.

  • But dry cleaning, like everything, comes with accidents.

  • And unlike a water spillage, a perc spillage can be harmful to the environment.

  • We don't have a great way to clean up perc chemical spills right now,

  • so we may need to get creative.

  • Industrial plants use some species of soil bacteria to clean up waste products like 1,2-dichloroethane.

  • These bacteria have an enzyme that removes the halogens through SN2 reactions,

  • replacing them with more palatable alcohols.

  • So the waste chemicals can be eaten by bacteria, processed, and even reused in things like plastic manufacturing.

  • Perc's double bond makes it unable to do an SN2 reaction, so it's a challenging compound for bioremediation.

  • But maybe someday, chemists, and hungry bacteria, could help with this pollution.

  • For now, let's dive deeper into SN1 and SN2 reactions to find out how substrate structure and other reaction conditions can help us pick a likely mechanism.

  • [Theme Music]

  • In episode 20, we learned about SN1 and SN2 pathways for substitution reactions.

  • Being able to figure out which one takes place will let us predict the correct reaction products.

  • Remember, SN1 has a carbocation intermediate and results in a mixture of stereoisomers if a chiral center is reacting.

  • The SN2 mechanism is a concerted process and gives inverted stereochemistry at a reacting chiral center.

  • There are three key players in our substitution reaction dance or merry-go-round or whatever visual you like:

  • An sp3 hybridized carbon substrate, a leaving group that can accept electrons as it departs from the molecule, and a nucleophile:

  • something with a lone pair or pi bond.

  • Recognizing good leaving groups can help us determine if a substitution reaction can take place.

  • For example, weak bases with strong conjugate acids are good leaving groups.

  • Weak bases are happy to float around by themselves in solution as anions.

  • Most halides fall into this category, because the pKas for HCl, HI, and HBr are big negative numbers.

  • Other good leaving groups are sulfonates, compounds that come from acids with negative pKa values.

  • They're big molecules, their electrons are spread out and stabilized by multiple resonance structures,

  • and they have special non-IUPAC names like tosylate, mesylate, and triflate.

  • If the group we want to leave doesn't want to let go of the carbon chain, substitution does not happen.

  • We call these poor leaving groups.

  • Poor leaving groups tend to be strong bases, which are less stable than weak bases out on their own in solution.

  • Examples of poor leaving groups include hydroxide, N-H-2-minus, C-H-3-minus, and hydride,

  • all with weak conjugate acids that have pKas above 12.

  • However, sometimes we can turn a poor leaving group into a good one and entice it to leave by protonating it.

  • Sort of like offering your friend candy to give you their spot on the SN1 merry-go-round.

  • So, like I just said, hydroxide is a poor leaving group.

  • But if we add a proton to it, the leaving group changes to water,

  • which is happy to swim away in solution, leave behind a carbocation, and get substituted by a nucleophilic bromide.

  • We need a good leaving group for both SN1 and SN2 to happen.

  • But in organic chemistry, we'll often be asked to choose which mechanism is more likely for a given substitution reaction.

  • So, let's look at three key factors that can help us decide whether to do SN1 or SN2.

  • The first, and most important, factor is the structure of the substrate.

  • Substrates with leaving groups on primary carbons use SN2.

  • Substrates with leaving groups on secondary carbons can use SN1 or SN2.

  • And substrates with leaving groups on tertiary carbons use exclusively SN1.

  • These guidelines will work for most molecules you'll come across in organic chemistry,

  • but there are important exceptions.

  • For one, this neopentyl primary substrate won't do an SN2 mechanism very smoothly.

  • Our leaving group is one carbon away from a sterically hindered tertiary carbon,

  • so backside attack is really tough and the reaction is too slow to be practical.

  • We also have substrates like perc, chloroethene, or chlorobenzene,

  • where the leaving group is directly attached to a double bond.

  • Substitution by SN1 or SN2 doesn't happen at all.

  • The sp2 geometry is all wrong for SN2 backside attack, and SN1 is pretty unfavorable too,

  • because the vinyl or phenyl carbocations that would have to form are high-energy.

  • And then, we have substrates with allylic and benzylic leaving groups:

  • a leaving group that's one sp3 carbon atom away from a double bond.

  • They use both SN1 and SN2 reaction mechanisms.

  • Looking at one of these compounds, we might say, "oh, there's a leaving group on a primary carbon, so it's gotta be an SN2 mechanism."

  • But depending on reaction conditions, like if there's an excellent leaving group,

  • a carbocation can form because it's resonance-stabilized.

  • That's the first step of an SN1 mechanism!

  • This resonance-stabilization of an intermediate cation is what makes allylic and benzylic substrates special.

  • It also makes things even more complicated for allylic substrates.

  • If a reaction proceeds by an SN1 mechanism, the two resonance forms of the carbocation intermediate can lead to a mixture of constitutional isomers as products.

  • On the other hand, benzylic substrates only give one substitution product because they don't react on the benzene ring.

  • After the structure of the substrate, the second key to picking a path is the role of the nucleophile.

  • The nucleophile in an SN2 reaction is an active participant in the rate-determining step.

  • In our merry-go-round analogy, they were the playground bully who pushed someone off rather than waiting for them to leave.

  • Nucleophilicity is a term to describe just how pushy the nucleophile's behavior is.

  • Atom size plays a key role in nucleophile strength.

  • The more polarizable the atom, the easier it is to get those electrons to attack and make a new bond.

  • So nucleophilicity increases moving down a group on the periodic table.

  • Halogens, which we talked about as good leaving groups, are also good nucleophiles.

  • And really strong nucleophiles are often charged, so thiolates, hydroxide, and alkoxides are all examples of strong bullies

  • or nucleophilesthat use SN2 mechanisms.

  • However, compounds like methanol, acetic acid, water, and other alcohols are relatively weak nucleophiles.

  • Even with lone pairs on an oxygen atom, these molecules are uncharged and are less nucleophilic than their deprotonated cousins.

  • They patiently wait to hop on the merry-go-round, and are more likely to promote an SN1 reaction.

  • And chunky sulfonates, which are good leaving groups, are very poor nucleophiles.

  • Their electrons are tied up in resonance, not available to attack and make new bonds to a substrate.

  • Our third and final key to help us decide between an SN1 and SN2 mechanism is the solvent.

  • Solvents are usually liquids that are able to dissolve other things,

  • like how perc dissolves clothing grime in dry cleaning and water dissolves table salt.

  • There are two classes of solvents we need to consider in substitution reactions:

  • polar protic and polar aprotic.

  • Polar protic solvents, like water and ethanol, both have a proton on an electronegative atom.

  • This type of polar bond with a proton lets them hydrogen bond to both cations and anions.

  • This is good for SN1 mechanisms because the rate-determining step is the substrate breaking up into ions.

  • So polar protic solvents favor the SN1 mechanism.

  • On the other hand, in an SN2 reaction, we need the nucleophile to be really available to push out the leaving group in the rate-determining step.

  • If our nucleophile is tied up by the solvent, it loses its pushing power and becomes weaker.

  • So a polar aprotic solvent, which has no available hydrogens, can't hydrogen bond to our nucleophile.

  • And an SN2 reaction is favored.

  • Polar aprotic solvents have atoms like oxygen or nitrogen with a partial negative charge, and a polar bond, just not to a hydrogen atom.

  • The polar bonds help these solvents dissolve organic compounds and the ionic nucleophiles often used in SN2 reactions.

  • Some examples of polar aprotic solvents are acetone, dimethylformamide, and dimethylsulfoxide, or DMSO.

  • I'm gonna be honest, evaluating these key reaction conditions can feel complicated, but here's a trick we can use:

  • Weak nucleophiles are often polar protic solvents and favor SN1.

  • Since they're protic, the reaction is carried out under acidic conditions or generates a molecule of acid as a byproduct.

  • So, when we see acid as a reactant or product, think SN1.

  • And on the flip side, reactions that take place under neutral or basic conditions tend to favor SN2!

  • We can summarize all we've learned by adding different types of nucleophiles to the table we started in episode 20:

  • Like I've mentioned over and over again, the best way to learn reaction mechanisms in organic chemistry is to practice.

  • So let's do some rapid fire problems.

  • We're going to put four substitution problems on screen and predict the likely mechanism and the products.

  • Then, we'll work through the answers, so pause right after the question if you want to solve them yourself.

  • Ready?

  • Here's the first problem, a reaction between a tosylate and sodium benzenethiolate, carried out in the solvent DMF:

  • We have a secondary substrate with an excellent leaving group, so there's no definitive answer there.

  • Our nucleophile is the real deciding factor:

  • we have sulfur, with a negative charge on a large atom.

  • So it's a strong nucleophile – a playground bully.

  • This reaction is SN2, which gives us the inversion of stereochemistry in our product.

  • Here's the second problem, a reaction between an alcohol and hydrochloric acid:

  • First of all, hydroxide is a poor leaving groupbut remember!

  • HCl is a strong acid that dissociates into H-plus and Cl-minus,

  • so there are protons floating around that can protonate the alcohol and make it an excellent leaving group: water.

  • We have two keys here:

  • a good leaving group, and a tertiary substrate that blocks backside attacks.

  • We get an SN1 reaction!

  • This is reinforced by our little trick: there's acid in the reaction, so think SN1.

  • The products are a mixture of the same and inverted stereochemistry at the reacting chiral carbon.

  • For our third problem, how about this iodide reacting with acetic acid?

  • Let's assume acetic acid is also our solvent here.

  • We have a secondary substrate:

  • a benzene ring with the leaving group separated from it by one sp3 carbon.

  • So actually, this is a benzylic substrate that can make a resonance-stabilized secondary carbocation.

  • That means it could do SN1 or SN2, and we have to look at another factor to make the final call.

  • Acetic acid is our weak nucleophile and our polar protic solvent.

  • And we clearly have acidic conditions.

  • All signs point to SN1!

  • Finally, our last problem, a reaction between a bromide and an acetylide anion:

  • Our substrate here is a primary alkyl bromide, which rules out SN1 right away because SN1 reactions can only happen with secondary or tertiary substrates.

  • To double-check, our nucleophile is the strongly basic acetylide anion and our solvent is polar aprotic.

  • That ticks all of the boxes for an SN2 reaction!

  • That's all we have for now, but keep practicing!

  • Nucleophilic substitution reactions are some of the most common reactions in organic chemistry so we'll see them again and again.

  • In this episode we learned that:

  • The main determining factor of SN1 or SN2 mechanism is the structure of the substrate

  • Weaker nucleophiles favor SN1 while stronger nucleophiles favor SN2

  • Polar protic solvents favor SN1 while polar aprotic solvents favor SN2

  • And acidic conditions characterize SN1 mechanisms, while neutral or basic conditions are typical of SN2

  • In the next episode, we'll add to our table even more as we learn about elimination reactions,

  • where groups are lost from the substrate.

  • 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.

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Substitution Reactions - SN1 and SN2 Mechanisms: Crash Course Organic Chemistry #21

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    陳逸睿 posted on 2021/07/28
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