Nucleophilic Substitution, Elimination

[MedPR]

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TLDR: 3 questions
1. Why do aprotic solvents increase nucleophile reactivity (please don't answer with "because protic solvents stabilize them")?
2. What is the shortcut for knowing if absolute configuration (R/S) is inverted in Sn2?
3. Why don't Ketones/Aldehydes undergo Sn1/Sn2?

I think I know the generic mechanisms pretty well, but not in a way that is useful for MCAT.

I understand the condition differences for SN2/E2 vs SN1/E1, but I'm not really clear on why or when elimination is more likely than substitution and vice versa. So I'll just go down the list EK provides since it is pretty comprehensive and clear.

The Nucleophile and the 5 S's.

Nucleophile: Sn2 requires/prefers a strong nucleophile. Nucleophile doesn't matter in Sn1. In other words, strong nucleophile (MeO-, EtO-, etc) = SN2.

Substrate: Sterically hindered & tertiary = Sn1. Methyl and primary = Sn2. Secondary could be either

Solvent: Protic = Sn1 for 2 reasons. It stabilizes the nucleophile, which prevents Sn2. It also stabilizes the carbocation which speeds up the RDS in Sn1. Aprotic = Sn2 because.. I don't know why. Hopefully someone can explain why nucleophiles are more reactive in aprotic solvents? I know that protic reduces reactivity, but not why aprotic increases reactivity.

Speed: Sn2 depends on [nu] and [substrate]. Sn1 depends only on [substrate] because the slow step is the leaving group falling off, so the nucleophile is not rate determining.

Stereochemistry: Sn2 = relative inversion (can someone tell me that Kaplan shortcut again? The one that tells you the only situation that you actually undergo absolute config inversion). Sn1 = racemization since the carbocation intermediate is planar and the nu can add from either side.

Skeleton rearrangement. Sn2 = no rearrangement. Sn1 = possible rearrangement (hydride, alkyl shift)

So that's easy, Sn1 and Sn2 are easy to differentiate as are E1 and E2.

This thread actually came from my other thread about nu addition for ketones/aldehydes vs nu substitution for carboxylic acids. I don't understand why/when a functional group would prefer addition over substitution.

TLDR: 3 questions
1. Why do aprotic solvents increase nucleophile reactivity (please don't answer with "because protic solvents stabilize them")?
2. What is the shortcut for knowing if absolute configuration (R/S) is inverted in Sn2?
3. Why don't Ketones/Aldehydes undergo Sn1/Sn2?

 

[milski]

This is based on reading only the TL;DR version.

Looking at my notes, H-bonding is supposed to slow down the nucleophiles in a protic solvent. There is a drawing of a nucleophile surrounded by H-bonds. I guess the idea is that in a protic solvent a lot of the nucleophile molecules are somewhat attached to other molecules via H-bonding and have harder time attacking the reactant. In the meantime, Sn1 still happens and ends up being favored in that case.

Sn2 always inverts the configuration at the place where the substitution happens. The only case where you would not have R/S inversion is when that place is not a stereo center - like a single iodine leaving from a terminal alkyl carbon.

Ok, I read your long version. Aprotics on their own dont' increase Sn2 reactivity, they just don't decrease it the way protics do. In other words, if you consider aprotics as your baseline, protics will slow down Sn2 and Sn1 will be prevailing.

As for ketons and similar - I don't have to know that until Thursday (final), so I'll wait to see what people knowing more than me would say.

 

[thestrokes14]

1. Why do aprotic solvents increase nucleophile reactivity (please don't answer with "because protic solvents stabilize them")?
2. What is the shortcut for knowing if absolute configuration (R/S) is inverted in Sn2?
3. Why don't Ketones/Aldehydes undergo Sn1/Sn2?


Answers for the last two:

2. The only way you can assign R or S to a stereocenter is if that center is chiral (4 different substitutents). If it is NOT a chiral center, there cannot be R or S assigned, and no inversion is technically taking place. However, if it is a chiral center, for example of R configuration, an SN2 reaction will convert this to an S chiral center every single time.
3. Ketones and aldehydes don't participate in SN1/SN2 reactions very often because they contain no good leaving groups. Alkyl groups (for ketones) and hydrogens (for aldehydes) are both poor leaving groups. Carboxylic acids ahve an OH group that can be protonated to H3O+, a great leaving group.

 

[MedPR]

This is based on reading only the TL;DR version.

Looking at my notes, H-bonding is supposed to slow down the nucleophiles in a protic solvent. There is a drawing of a nucleophile surrounded by H-bonds. I guess the idea is that in a protic solvent a lot of the nucleophile molecules are somewhat attached to other molecules via H-bonding and have harder time attacking the reactant. In the meantime, Sn1 still happens and ends up being favored in that case.

Sn2 always inverts the configuration at the place where the substitution happens. The only case where you would not have R/S inversion is when that place is not a stereo center - like a single iodine leaving from a terminal alkyl carbon.

Ok, I read your long version. Aprotics on their own dont' increase Sn2 reactivity, they just don't decrease it the way protics do. In other words, if you consider aprotics as your baseline, protics will slow down Sn2 and Sn1 will be prevailing.

As for ketons and similar - I don't have to know that until Thursday (final), so I'll wait to see what people knowing more than me would say.

1. Why do aprotic solvents increase nucleophile reactivity (please don't answer with "because protic solvents stabilize them")?
2. What is the shortcut for knowing if absolute configuration (R/S) is inverted in Sn2?
3. Why don't Ketones/Aldehydes undergo Sn1/Sn2?


Answers for the last two:

2. The only way you can assign R or S to a stereocenter is if that center is chiral (4 different substitutents). If it is NOT a chiral center, there cannot be R or S assigned, and no inversion is technically taking place. However, if it is a chiral center, for example of R configuration, an SN2 reaction will convert this to an S chiral center every single time.
3. Ketones and aldehydes don't participate in SN1/SN2 reactions very often because they contain no good leaving groups. Alkyl groups (for ketones) and hydrogens (for aldehydes) are both poor leaving groups. Carboxylic acids ahve an OH group that can be protonated to H3O+, a great leaving group.

Ok, a couple of things. R/S inversion does not always occur with chiral centers. I did some searching and found the thread about it. Inversion of RELATIVE configuration ALWAYS occurs in SN2, but inversion of ABSOLUTE (R/S) configuration ONLY occurs if the LG and Nu are the same priority. Otherwise ABSOLUTE config is retained, though there is inversion of relative configuration. http://forums.studentdoctor.net/showthread.php?t=880564

Second, I've read in a few places that aprotic solvents increase reactivity of all nucleophiles. The reason why they are important in sn2 is mostly because protic solvent stabilizes nucleophiles. The latter is probably all you need to know and understand for the MCAT, but seeing "aprotic increases nucleophile reactivity" and not being able to figure out why is really bothering me. I remember my ochem 1 teacher saying that polar solvents increased nucleophile reactivity overall, but I can't remember what the explanation was.

In regard to the ketone/aldehyde stuff, why do they undergo addition? Don't E1 and E2 require good leaving groups too?

 

[thestrokes14]

Ok, a couple of things. R/S inversion does not always occur with chiral centers. I did some searching and found the thread about it. Inversion of RELATIVE configuration ALWAYS occurs in SN2, but inversion of ABSOLUTE (R/S) configuration ONLY occurs if the LG and Nu are the same priority. Otherwise ABSOLUTE config is retained, though there is inversion of relative configuration. http://forums.studentdoctor.net/showthread.php?t=880564

Second, I've read in a few places that aprotic solvents increase reactivity of all nucleophiles. The reason why they are important in sn2 is mostly because protic solvent stabilizes nucleophiles. The latter is probably all you need to know and understand for the MCAT, but seeing "aprotic increases nucleophile reactivity" and not being able to figure out why is really bothering me. I remember my ochem 1 teacher saying that polar solvents increased nucleophile reactivity overall, but I can't remember what the explanation was.

In regard to the ketone/aldehyde stuff, why do they undergo addition? Don't E1 and E2 require good leaving groups too?

First of all, you are right about the R/S conversion. In the end, it depends on the priority of the nucleophile relative to the priority of the leaving group. That being said, good nucleophiles (like OH-) typically have HIGH priority, so in most cases, the inversion happens. Always double check, though.

Aprotic solvents are polar solvents, as are protic solvents. But protic solvents are like very strongly polar (with the potential of hydrogen bonding). Polar protic solvents are so polar that they can stabilize carbocations that result from leaving groups (SN1). Aprotic solvents cannot do this nearly as well, so leaving groups are more inclined to just not leave (remember, this leaving process is in equilibrium), thus promoting SN2 reactions.

 

[milski]

Ok, a couple of things. R/S inversion does not always occur with chiral centers. I did some searching and found the thread about it. Inversion of RELATIVE configuration ALWAYS occurs in SN2, but inversion of ABSOLUTE (R/S) configuration ONLY occurs if the LG and Nu are the same priority. Otherwise ABSOLUTE config is retained, though there is inversion of relative configuration. http://forums.studentdoctor.net/showthread.php?t=880564

Dang, you're right. Physically, the inversion happens all the time. But since you're replacing one of the C substituents you can change their priority. I cannot think about a good general shortcut in this case, since the result will depend on where the new substituent ends up. There may be something which takes into account that there's only limited amount of LG/Nu combinations but I have not seen it before.

Second, I've read in a few places that aprotic solvents increase reactivity of all nucleophiles. The reason why they are important in sn2 is mostly because protic solvent stabilizes nucleophiles. The latter is probably all you need to know and understand for the MCAT, but seeing "aprotic increases nucleophile reactivity" and not being able to figure out why is really bothering me. I remember my ochem 1 teacher saying that polar solvents increased nucleophile reactivity overall, but I can't remember what the explanation was.

I think this is more about semantics than anything. Protics increase it because aprotics decrease it. You don't have an intermediate to compare to anyway, so any increase is only compared to aprotics. You can say that the protics don't 'slow down' the nucleophile and allow it proceed as fast as it can.

 

[MedPR]

First of all, you are right about the R/S conversion. In the end, it depends on the priority of the nucleophile relative to the priority of the leaving group. That being said, good nucleophiles (like OH-) typically have HIGH priority, so in most cases, the inversion happens. Always double check, though.

Aprotic solvents are polar solvents, as are protic solvents. But protic solvents are like very strongly polar (with the potential of hydrogen bonding). Polar protic solvents are so polar that they can stabilize carbocations that result from leaving groups (SN1). Aprotic solvents cannot do this nearly as well, so leaving groups are more inclined to just not leave (remember, this leaving process is in equilibrium), thus promoting SN2 reactions.

Yea, I certainly understand why aprotics don't hinder the nucleophiles and why/how protics stabilize them, I'm just trying to figure out why polar aprotic is better for sn2 than a nonpolar solvent.

I think this is more about semantics than anything. Protics increase it because aprotics decrease it. You don't have an intermediate to compare to anyway, so any increase is only compared to aprotics. You can say that the protics don't 'slow down' the nucleophile and allow it proceed as fast as it can.

I think you mean aprotics in that last sentence. And yea I guess you're right about the relative nature of those statements.

 

[chiddler]

Yea, I certainly understand why aprotics don't hinder the nucleophiles and why/how protics stabilize them, I'm just trying to figure out why polar aprotic is better for sn2 than a nonpolar solvent.



I think you mean aprotics in that last sentence. And yea I guess you're right about the relative nature of those statements.

A nonprotic solvent won't allow a leaving group to exist. They usually leave as ions, yes? So a non-protic will hinder all reaction because LG cannot leave.

And what exactly is your question regarding aldehydes and ketones? They are certainly capable of nucleophilic addition. And what is the relevance to E1/2?

 

[MedPR]

A nonprotic solvent won't allow a leaving group to exist. They usually leave as ions, yes? So a non-protic will hinder all reaction because LG cannot leave.

And what exactly is your question regarding aldehydes and ketones? They are certainly capable of nucleophilic addition. And what is the relevance to E1/2?

Ok so the polar aprotic solvents can stabilize anions but can't stabilize cations? Why?

It's basically the same question as the thread devoted to it, however, I realized what I was doing and I'm glad you pointed it out. I had it in my head that "nucleophilic addition" meant "E1/E2." That's why I was confused because I couldn't see why E1/E2 would occur but Sn1/Sn2 wouldn't.

 

[milski]

I think you mean aprotics in that last sentence. And yea I guess you're right about the relative nature of those statements.

Yes, I meant aprotics. That's one thing thing that kills me on tests. Going through reasoning like A increases because B decreases because C increases tends makes me lose track of what's increasing and what's decreasing in no time. And there's so much of that in o-chem.

 

[chiddler]

Ok so the polar aprotic solvents can stabilize anions but can't stabilize cations? Why?

It's basically the same question as the thread devoted to it, however, I realized what I was doing and I'm glad you pointed it out. I had it in my head that "nucleophilic addition" meant "E1/E2." That's why I was confused because I couldn't see why E1/E2 would occur but Sn1/Sn2 wouldn't.

It can do both.

your question is why does polar aprotic favor SN2 and why does polar protic favor SN1?

 

[MedPR]

It can do both.

your question is why does polar aprotic favor SN2 and why does polar protic favor SN1?

If aprotics can stabilize anions, then why don't they slow down Sn2?

Not exactly. I know why protic pushes toward Sn1 and therefore reduces Sn2. I also know that your choices are either protic or aprotic, and since protic is bad for Sn2, you are left with aprotic as your only option. I've read that aprotic solvents increase nucleophilicity, but I don't know why and I would like to know why.

 

[chiddler]

If aprotics can stabilize anions, then why don't they slow down Sn2?

Not exactly. I know why protic pushes toward Sn1 and therefore reduces Sn2. I also know that your choices are either protic or aprotic, and since protic is bad for Sn2, you are left with aprotic as your only option. I've read that aprotic solvents increase nucleophilicity, but I don't know why and I would like to know why.

because they do not stabilize them as well as protics.

in SN1, the intermediate is relatively high energy and requires a lot of support to exist. This is why protics favor, not allow, SN1 to occur.

Aprotic solvents will probably allow SN1 as well, but to a much lesser extent because the carbocation intermediate cannot be stablized as well by the less polar solvent.

Second question: They increase nucleophilicity for this same reason. A nucleophile exists as an ion in solution. If it is in a protic solvent, then it will latch onto the solvent very strongly since it is so polar. It becomes more difficult to release the nucleophile to react.

In an aprotic, the nucleophile can exist without the many hands of the solvent holding it back.

 

[MedPR]

because they do not stabilize them as well as protics.

in SN1, the intermediate is relatively high energy and requires a lot of support to exist. This is why protics favor, not allow, SN1 to occur.

Aprotic solvents will probably allow SN1 as well, but to a much lesser extent because the carbocation intermediate cannot be stablized as well by the less polar solvent.

Second question: They increase nucleophilicity for this same reason. A nucleophile exists as an ion in solution. If it is in a protic solvent, then it will latch onto the solvent very strongly since it is so polar. It becomes more difficult to release the nucleophile to react.

In an aprotic, the nucleophile can exist without the many hands of the solvent holding it back.

Ok let's see.

I understand why protics favor Sn1 and hinder Sn2.

I understand why aprotics don't help Sn1 very much.

I understand that a protic solvent will stabilize the nucleophile, thus hindering Sn2 but not affecting Sn1 since the nucleophile is not part of the rate limiting step.

I understand why an aprotic solvent would not hinder Sn2 like protic would, but what does an aprotic do for Sn2 that a nonpolar solvent doesn't? Sorry if you already answered this, I just can't seem to grasp it.

 

[chiddler]

hey by the way we're only talking about favorability! thermodynamic discussion. slow down and speed up is kinetics and is a much simpler subject.

 

[chiddler]

The aprotic solvent does not allow the carbocation intermediate to exist easily. Therefore, SN1 can not occur much.

A protic does allow it to exist much more easily because the solvent bonds are a lot more polar and the stronger partial charges make the carbocation more favorable.

 

[MedPR]

The aprotic solvent does not allow the carbocation intermediate to exist easily. Therefore, SN1 can not occur much.

A protic does allow it to exist much more easily because the solvent bonds are a lot more polar and the stronger partial charges make the carbocation more favorable.

I know.

The only thing I don't know is why polar aprotic is better than nonpolar for Sn2. In nonpolar, the nucleophile is going to be unstable and more reactive, which should be a good thing for Sn2, right?

 

[chiddler]

I know.

The only thing I don't know is why polar aprotic is better than nonpolar for Sn2. In nonpolar, the nucleophile is going to be unstable and more reactive, which should be a good thing for Sn2, right?

Polar aprotic does not allow SN1 to occur. The only other option is SN2.

a non polar wouldn't allow ions to exist! can't dissolve salt in oil

 

[thestrokes14]

Yeah, the kinetic effect takes over once you get into the nonpolar solvents. Activation energy is going to skyrocket, making the reaction very slow (even though thermodynamically, the reactants and products remain the same).

 

[MedPR]

Polar aprotic does not allow SN1 to occur. The only other option is SN2.

a non polar wouldn't allow ions to exist! can't dissolve salt in oil

Yeah, the kinetic effect takes over once you get into the nonpolar solvents. Activation energy is going to skyrocket, making the reaction very slow (even though thermodynamically, the reactants and products remain the same).

Oh, right. Thanks 😀