Its all about electrons

Its all about electrons. Electrons rule everything in organic chemistry. As well see, electrons and electron density explain just about everything we need to know for substitution and elimination reactions. Having a good understanding of where to find electron density and how electron density stabilizes or destabilizes molecules will help us decide when a reaction will follow one pathway versus another.

See, the thing is, electrons are like a hyperactive child. If you put a hyperactive child in a small room hes going to play with his truck, he wants to show you the truck, he wants a cookie, he needs to go to the bathroom, HesGonnaPlayWithTheTruckAgain, HESGONNABREAKTHETRUCK, HESGONNARUNAROUNDTHEROOMSCREAMING AAAHHH!

A hyperactive child in a small room is going to be bouncing off the walls! Driving everyone crazy! Its a very unstable situation.

But if you throw that child out in the backyard hes got plenty of room to run around everyones happy everything is just more calm and under control that way. Its much more stable.

Electrons are the same way. If you try to jam a lot of electron density IntoAVerySmallVolume, ALLTHATENERGYMAKESTHEMOLECULEUNSTABLE!!Electrons do not like to be confined in a very small volume.

But, if you spread that electron density out, say by delocalizing it over several atoms through resonance, the electrons have more room to run around, and they are much more stable, and we all can breathe a sigh of relief. Its much more stable. This holds for charge density in general, whether negative charge density or positive charge density. We will want to keep this analogy in mind as we try to find a rational way to make sense of these reactions without resorting to memorizing.

There arefour main componentswe will need to address in order to understand substitution and elimination reactions:the nucleophile, the electrophile, the leaving group, and the solvent.Understanding how the functional groups in each of these components modulate electron density will be the key to unlocking the mystery of substitution and elimination. Different nuances in each component serve to either concentrate electron density into a smaller volume, or spread electron density out over a larger volume, and this difference can push a reaction to follow one path or another.

But this is also the source of the greatest confusion, so Ill warn you about it upfront. All of these components will start to look the same after a while, and it will look like some seemingly minor change in a molecule will completely change the outcome of the otherwise identical reaction! How are we supposed to keep it all straight?

By being good diagnosticians. In fact, congratulations! Youve just been hired as the newest doctor on Dr. Gregory Houses crack team! (pretend theyre bringingthe showback) They always take the hardest, most confusing cases where the symptoms seem to point in contradictory directions. They have to dig through all the symptoms to find all the evidence, then figure out how all the parts fit together to arrive at a brilliant diagnosis. These reactions are your House Patients. Its up to you to assess all the evidence to come up with the brilliant diagnosis of the correct reaction pathway.

And thats how the rest of the posts in this series are going to go. Ill introduce all the major systems and components. Well look at what evidence we can gather from the leaving group, the nucleophile, the electrophile, and the solvent, and Ill show you how to assess all the evidence as a whole to diagnose the reaction.

My next post was going to cover the 4 possible mechanisms and the evidence for each, but I noticed James already has a fantastic round up of the substitution (SN1andSN2) and elimination (E1andE2) mechanisms. I dont have anything to add to these posts, so I wont repeat content James already has. Instead, between this post and the next post, I want you to look over James write up of the four mechanisms. Make sure youre familiar with the four mechanisms, and well pick up next time with assessing the leaving group.

3 Steps To Any Substitution Or Elimination Reaction. Step (): What is the nature of the leaving group? by @azmanam

If you havent looked through James fantastic posts over the four possible mechanisms (SN1,SN2,E1,E2), be sure to go back and read them before todays installment.

Our first (half) step is toassess the nature of the leaving group. This is a relatively quick step and ensures we can even perform one of these reactions. For substitution/elimination reactions, the leaving group must satisfy two conditions. It must be a good leaving group, and it must be attached to an sp3hybridized carbon atom.

What does it mean to be a good leaving group? Remember from our first post that it all has to do with the electrons. If we can rationalize these reactions in terms of electrons and electron density and stability, we can predict how these reactions will play out.

So we need to think about what happens to the leaving group during the reaction and what factors will make this better or worse. These reactions are of a nucleophile/base with an electrophile bearing a leaving group to perform a substitution or elimination reaction but in either case the leaving group is expelled along with a pair of electrons.

This is important:when the leaving group leaves, it gains a new lone pair of electrons and an excess of electron density.For a leaving group to be a good leaving group, it would have to accept this new glut of electron density with ease. A bad leaving group would have to become significantly unstable with this new electron density.A good leaving group is able to stabilize this excess electron density, and a bad leaving group is not.

Lets take a look at the following potential leaving groups. Lets look at the good leaving groups versus the bad leaving groups and see how electron density stability helps explain the ranking of these leaving groups.

When the leaving group leaves, it leaves with the pair of electrons that used to be in the bond. How the leaving group handles that sudden build up in electron density determines whether the leaving group will be a good or bad leaving group. Remember that its all about electron density which is like a hyperactive child. If that electron density can be spread out over a larger volume of our leaving group, it will be a more stable and better leaving group than if the electron density cannot be spread out and is forced to be concentrated in a very small volume.

Side note: there is another phenomenon that works by this same thought process:base strength. When an acid gets deprotonated and gets turned into its conjugate base, it accepts a pair of electrons and extra electron density. The more stable the electrons, and the more stable the base, the weaker the base will be.

This leads to a convenient mnemonic for substitution and elimination reactions:the best leaving groups are the weakest bases. Cl, Br, MsO(OSO2CH3) are all weak bases and fantastic leaving groups.

The other criterion a leaving group has to meet is the nature of the carbon atom to which it is attached. The carbon atom must be sp3hybridized. For our purposes in introductory organic chemistry, substitution and elimination will not occur at sp2 or sp-hybridized carbon atoms.

So our first (half) step to determining which substitution or elimination reaction will occur is to do a quick check to make sure the leaving group is a good leaving group (a weak base) and that the leaving group is attached to an sp3-hybridized carbon atom. If even one of these criteria is not met, no substitution or elimination reaction will happen. If both of these criteria are met, it doesnt help us decide which of the four reactions occur, but we can move on to the next three steps to figure out which of the four reactions is the one that will take place. The first big step well take is to assess the nature of the nucleophile, and that will be the topic of the next post.

Step One: What is the nature of the nucleophile? by @azmanam

Last time, we talked about the quick check on the nature of the leaving group. Today, well discuss how the nature of the nucleophile helps our chemical differential diagnosis. If its all about the electrons, and if concentrating more and more electron density into a smaller and smaller volume makes a molecule less stable, then we can use this information to help us assess the nature of the nucleophile.

Reviewing the four possible mechanisms, the nucleophile plays a big role in the reaction. It is the piece with all the electron density. It is the molecule which will be attacking the electrophile to form the new bond.It is the actor in these reactions, and we need to be able to assess its strength before we can decide the appropriate mechanism.

Lets look at the 2 mechanisms first: theSN2and theE2. In these reactions,the nucleophile directly attacks the electrophileto start out the mechanism. It either directly attacks the electrophilic carbon atom or the -hydrogen atom, but it has to have enough inherent energy to be strong enough to directly attack the electrophile.

The opposite is true in the 1 mechanisms. In theSN1andE1, the nucleophile does not directly attack. Instead,the nucleophile has to wait around until the leaving group decides to leave, and only then will the nucleophile attack the much more unstable carbocation. If the nucleophile doesnt have the inherent energy to directly attack, it must be a considerably weaker nucleophile compared to the 2 mechanisms.

So we can already say thatstrong nucleophiles will be evidence for the 2 mechanisms, and weak nucleophiles will be evidence for the 1 mechanisms. But its a bit more nuanced than that, because sometimes the nucleophile attacks the electrophilic carbon, and sometimes it attacks the -hydrogen. Sometimes it acts as a nucleophile, and sometimes it acts as a base.

So what makes something a strong or a weak nucleophile, and what makes it act more as a nucleophile or as a base? Both variables are continuums, and there are many shades of gray, but we can discuss some generalities which will help us diagnose this reaction.

Electrons do not like to be confined. It makes the electrons more unstable, and the molecule more unstable. Strong nucleophiles and bases are characterized by lots of electron density (usually so much electron density that it has a full negative charge) in a very small volume. You may remember this trend from the acid/base chapter characterizing strong bases. In general, nucleophile strength parallels base strength. So in general strong nucleophiles will also be strong bases. Here are some molecules we would characterize as strong nucleophiles/strong bases:

Of course, there are some exceptions, not every strong base will also be a strong nucleophile, and vice versa. So what factors might make something strong in one category, but weak in another? And why is there a difference anyway? Its subtle, but there is a difference because basicity is a thermodynamic property (the acid/base equilibrium favors the weaker base), but nucleophilicity is a kinetic property (the rate at which a nucleophile reacts with an electrophile).

Steric hindrance makes a molecule a weaker nucleophile. In order for a nucleophile to attack an electrophilic carbon atom, it has to get close enough to that carbon atom in the interior of the molecule, and bulky nucleophiles have a harder time doing that. The prototypical non-nucleophilic base is potassiumtert-butoxide, KOtBu. With the full negative charge localized on the single oxygen atom, it is a strong base, but the steric bulk from the methyl groups makest-butoxide a rather poor nucleophile. Other non-nucleophilic bases include NaH, LDA, and DBU.

The conjugate bases of the mineral acids make good nucleophiles, but terrible bases. Brand Iare all pretty good nucleophiles, but pretty bad bases. Other molecules with anegative charge on a single atom, but a strong conjugate acid make good nucleophiles, but weak bases. The cyanide anion, the azide anion, and thiolates also make a great nucleophile, but tend to be a poor base.

So if negative charges concentrated in a very small volume make a molecule a strong nucleophile and base, the opposite characteristics will make something aweak nucleophile and base: neutral charges, electron density spread over a large volume (say, through resonance), and very low conjugate acid pKas.

Neutral alcohols, neutral carboxylic acids, neutral thiols, and even carboxylate anions (with the electron density stabilized through resonance) make weak nucleophiles and weak bases. These molecules do not have the strength to directly attack an electrophile, so they must wait around until the leaving group decides to leave and form a very unstable carbocation before the nucleophile can attack.

So remember,its all about electron density does this nucleophile have a lot of electron density (maybe even a full negative charge) concentrated in a very small volume? Or are the electrons more stable or spread out over a larger volume? Learning these trends will help us figure out what evidence we get about our diagnosis from the nucleophile. The nucleophile will fall into one of four categories: strong nuc/strong base, strong nuc/weak base, weak nuc/strong base, weak nuc/weak base. And the different categories are evidence for and against different possible mechanisms. Lets start a chart. Well fill in more of this chart as we assess the electrophile and the solvent, but well start with the nucleophile:

Nuc Category

Evidence For

Evidence Against

Strong nuc/strong base

SN2, E2

SN1, E1

Strong nuc/weak base

SN2

SN1, E1, E2

Weak nuc/strong base

E2

SN1, SN2, E1

Weak nuc/weak base

SN1, E1

SN2, E2

Lets answer one interesting question before we finish for the day: Why wouldnt a strong nuc/weak base be evidence for SN2 and E1? And why wouldnt a weak nuc/strong base be evidence for SN1 and E2? Becausethe nucleophiles are the actorsin these reactions. To be a 1 reaction, the nucleophile has to wait around long enough for the leaving group to spontaneously leave on its own. If the nucleophile is strong enough to invoke one of the 2 mechanisms without having to wait around for the carbocation, that mechanism will dominate it wont give the electrophile enough time to form the carbocation. It doesnt have to. It has plenty of excess energy more than enough to go straight to the 2 mechanism.

A word of caution: even though some of the nucleophiles are only evidence for one mechanism,we stillmustassess all the evidence before we make a diagnosis. Do you remember the episode ofHousewhereDr. House teaches the diagnosis class for a day? He opens class by announcing that 3 patients enter the clinic complaining of leg pain. What should they do? The first eager med student shoots his hand up and says ice, rest, and elevate. Dr. House acknowledges that most leg pain is a result of minor sprains and strains, but if the doctor gives that advice to these three patients, within 24 hours they will all be dead. The point of the story is we need all the symptoms and all the evidence from those symptoms before we attempt a diagnosis.

Next time, well learn how to read the electrophile and figure out what evidence the electrophile gives us.

Step 2: What is the nature of the electrophile?

The nature of the electrophile is a bit simpler to assess than the nucleophile. We need to know what the degree of substitution is for the electrophilic carbon atom. Recall that the degree of substitution of a carbon atom is equal to the number ofothercarbon atoms to which it is attached. The degree of substitution for several carbon atoms is listed below.

To rationalize the evidence we gain from the electrophile, we need to remember how the various mechanisms work. For the SN2 reaction, the nucleophile has to be able to get all the way to the interior of the molecule and get close enough to the electrophilic carbon atom to directly attack and form a new bond. For the SN1 and E1, the leaving group has to leave first to form an unstable carbocation. And for the E2, the base deprotonates the -carbon atom adjacent to the electrophilic carbon atom.

Different degrees of substitution for electrophiles will facilitate our substitution and elimination mechanisms to a different extent. Tertiary electrophiles are too sterically hindered to allow the nucleophile to get close enough for direct substitution attack, but methyl, primary, and secondary are fine. Methyl and primary electrophiles are too un-substituted to allow a carbocation to form, but secondary and tertiary are ok. Methyl electrophiles dont even have a -carbon atom for elimination, but the rest do. So these are the things we think about to help us figure out the evidence we gain from the electrophiles.

Electrophile Category

Evidence For

Evidence Against

Methyl

SN2

SN1, E1, E2

Primary

SN2, E2

SN1, E1

Secondary

SN1, SN2, E1, E2

Tertiary

SN1, E1, E2

SN2

Note that the secondary electrophile is evidence for all possible mechanisms it doesnt help us narrow down our decision. We will need to rely on our other pieces of evidence more in this circumstance.

A common question is: why is a tertiary electrophile evidence for E2? I thought it was sterically hindered! It is but we need to remember how the mechanism works. The E2 reaction works by the strong base attacking the proton on the -carbon atom. The -proton is two whole bonds away from the hindered electrophilic carbon atom and is on the periphery of the molecule. It is not nearly as difficult for a strong base to attack a peripheral proton versus making it all the way to the interior of the molecule to act as a nucleophile and attack the electrophilic carbon atom.

We need to make one more point about carbocations before we break for the day. Carbocations that can be stabilized by resonance are more stable than their degree of substitution would suggest. To a first approximation, the ability to stabilize a primary carbocation by resonance will make the carbocation about as stable as a secondary carbocation. In general, resonance stabilization bumps up the carbocation stability by one level. Thus a resonance stabilized primary carbocation is stable enough to form and engage in SN1 and E1reactions. Always be on the lookout for resonance!

Step 3: What is the nature of the solvent?

You might think the solvent shouldnt have much influence on a reaction mechanism. Its whole job is to just dissolve the reagents, right? Well, yes, but solvents can also modulate the electron density within a reagent. And by now, we all know its all about the electron density. Some solvents have the ability to diffuse electron density over a larger volume, and some solvents can concentrate electron density. Can you see where were going here? More electron density will make nucleophiles and bases stronger than they otherwise would have been, and diffused electron density will make nucleophiles and bases weaker than they otherwise would have been.

There are three main classes of solvents for organic reactions: nonpolar solvents, polar protic solvents, and polar aprotic solvents. James already has a nice roundup of these classes of solvents, and you shouldread his postbefore reading on. Since most SNand E reactions utilize polar reagents, we typically dont see nonpolar solvents for these reactions very often. So lets focus on the polar solvents.

Polar solvents have some permanent net dipole. What separates a polar protic solvent from a polar aprotic solvent is the presence or absence of a hydrogen atom capable of hydrogen bonding; some hydrogen atom attached to an electronegative element (typically oxygen) which can engage in a hydrogen bond. Polar protic solvents have this hydrogen atom, and polar aprotic solvents lack this hydrogen atom.

Polar protic solvents are typically alcohols, water, or carboxylic acids. Polar aprotic solvents include ethers and carbonyl-containing molecules such as ketones (usually acetone), amides (usually dimethylformamide), and a few specific solvents like acetonitrile and dimethylsulfoxide.

How these solvents interact with nucleophiles and electrophiles (specifically carbocations) will influence the amount of electron density in a molecule, and this can sometimes have an impact on the mechanism.

Polar protic solvents have a hydrogen atom which can hydrogen bond with the lone pair in a nucleophile. That lone pair is now not as concentrated locally on the nucleophile. Now that electron density is spread out over a slightly larger volume as it shares some electron density with the hydrogen atom of the solvent. This makes the nucleophile slightly weaker than it otherwise would be.

At the same time that the polar protic solvent is stabilizing the nucleophile, it also has the ability to stabilize any carbocations formed during the reaction. The lone pair of electrons on the solvent can donate electron density to the carbocation, making the carbocation more stable. A weaker nucleophile and a stabilized carbocation mean that polar protic solvents are evidence for SN1 and E1 reactions.

Polar aprotic solvents, by contrast, cant hydrogen bond with nucleophiles. For ionic nucleophiles, though, polar aprotic solvents can stabilize the counter cation to the nucleophile. So with no nucleophile stabilization other than some dipole-dipole interactions, the electron density on the nucleophile is not diffused to a great extent like the protic solvents, and polar aprotic solvents tend to be evidence for SN2 reactions.

A couple of notes about the evidence we gain from solvents. I dont like to say that solvents are evidenceagainstany mechanism. It is often possible to carry out, for instance, an SN2 reaction in a polar protic solvent, and other examples of mismatched solvents can be found. Use solvents more to corroborate evidence you already have, or as a tie breaker if needed. Did you notice the E2 mechanism wasnt listed above? Remember that nucleophilicity and basicity are closely related, but they are different concepts. It turns out that polar protic solvents diminish nucleophilicity a lot, but diminish basicity to a lesser extent. This information can be useful when trying to decide between an SN2 and E2 mechanism with a strong nuc/strong base. In general, polar protic solvents favor elimination, while polar aprotic solvents tend to favor substitution.

Solvent classification

Evidence for

Evidence against

Polar protic

SN1, E1, E2

Polar aprotic

SN2

One final note that fits best here, even though its not a solvent. In general, all else being equal, elevated temperatures tend to favor elimination reactions. The extra energy from the heat gives the reaction just enough boost to form the double bond product. So if all our evidence contradicts, or if the evidence points in two clear directions, the temperature (if given) can help us decide which will be the major organic product. Although a mixture of products will likely form if everything else really is equal.

Thats it! We now have all the evidence we need to determine the mechanism for our substitution/elimination reactions. Next time, well see how to pull it all together and start predicting some products!

Lets review what weve learned so far.1)Electrons dont like to be confined. The more electron density you have in a small volume, the more unstable the molecule will be.2)The leaving group must be able to accept a pair of electrons and be stable when it leaves. The best leaving groups are weak bases. Beware, the leaving group must be located on an sp3-hybridized carbon atom.3)Strong nucleophiles and strong bases have lots of electron density concentrated in a very small volume.4)Electrophiles are classified based on two variables: steric hindrance of the electrophilic carbon atom, and ability to form a relatively stable carbocation.5)Solvents can either diffuse electron density or concentrate electron density, and can be used as a tie-breaker if needed.

Each piece of the reaction provides us different evidence for or against certain mechanisms. Here is the chart weve been building over the last couple of posts.

Classification

Evidence for

Evidence against

Nucleophile

Strong nuc/strong base

SN2, E2

SN1, E1

Strong nuc/weak base

SN2

SN1, E1, E2

Weak nuc/strong base

E2

SN1, SN2, E1

Weak nuc/weak base

SN1, E1

SN2, E2

Electrophile

Methyl

SN2

SN1, E1, E2

Primary

SN2, E2

SN1, E1

Secondary

SN1, SN2, E1, E2

Tertiary

SN1, E1, E2

SN2

Solvent

Polar protic

SN1, E1, E2

Polar aprotic

SN2

Now its just a matter of assessing the evidence from each piece of the reaction and making the diagnosis.

There are two final questions that must be addressed before we leave. What if the leaving group is attached to a stereocenter? And what if the carbocation can rearrange? The answer to the first question depends on which mechanism we are invoking. For the SN2, because the nucleophile must specifically approach the electrophile from a trajectory 180 opposed to the leaving group, the stereocenter will be inverted. For the E2, the leaving group and the -proton must be anti-coplanar (this can sometimes be best viewed in a Newman projection or chair structure), and will lead to a specificEorZalkene depending on the other groups on the electrophile. For the SN1 and E1, the intermediate carbocation can be attacked from either face of trigonal plane and has free rotation about all single bonds, so we tend to form a mixture of stereoisomers in the SN1 reaction, and due to steric reasons typically the isomer with the large groups trans in the E1.

What if the carbocation can rearrange? Well, only SN1 and E1 even form carbocations, so we only need to answer this question if we decide were using one of these mechanisms. Carbocations are inherently unstable, and carbocation will only rearrange if we can sacrifice an unstable carbocation to gain a more stable carbocation. Alkyl groups and resonance stabilize carbocations. So we will only rearrange a carbocation if we can increase the number of alkyl groups and/or stabilize the carbocation through resonance. Hydride (H) and alkyl groups are the most common groups to migrate, if rearrangement can occur.

Want some examples? OK! Some of these are more straight forward, and some will force you to make decisions based on conflicting evidence!

So enjoy your newfound expertise with substitution/elimination mechanisms. Remember, if you bring everything back to electron density, it all starts to make sense.

Question 1: Is the carbon containing the leaving group methyl (only one carbon), primary, secondary, or tertiary?

Quick N Dirty Rule #1: If primary, the reaction will almost certainly be SN2[prominent, commonly encountered exceptions: 1) a bulky base such as tBuOK will tend to give elimination products [E2]; 2) primary carbons that can form relatively stable carbocations may proceed through the SN1/E1 pathway.] Also methyl carbons always proceed through SN2.

Quick N Dirty Rule #2: If tertiary, the reaction cannot be SN2.[Because tertiary alkyl halides are too hindered for the SN2. Depending on the type of nucleophile/base, it will either proceed with concerted elimination [E2] or through carbocation formation [SN1/E1]

Question 2: Does the nucleophile/base bear a negative charge?

Quick N Dirty Rule #3: Charged nucleophiles/bases will favor SN2/E2 pathways[i.e. rule out SN1/E1]. [So, for example, if SN2 has already been ruled out [e.g. for a tertiary carbon, according to Question 1] then the reaction will therefore be E2. This is the case for tertiary alkyl halides in the presence of strong bases such as NaOEt, etc. The strength of the [charged] nucleophile/base can be important! An important special case is to be aware of charged species that are weak bases [such as Cl, N3,CN, etc.] these will favor SN2 reactions over E2 reactions].

Quick N Dirty Rule #4: If a charged species isnotpresent, the reaction is likely to be SN1/E1.[so if the only reagent is, say, H2O or CH3OH you are likely looking at carbocation formation resulting in an SN1/E1 reaction.]

Question 3: Is the solvent polar protic or polar aprotic?

Quick N Dirty Rule #5: All else being equal, polar aprotic solvents favor substitution [SN2] over elimination [E2]. Polar protic solvents favor elimination [E2] over substitution [SN2].[Note that this rule is generally only important in the case of trying to distinguish SN2 and E2 with a secondary alkyl halide and a charged nucleophile/base. This is not meant to distinguish SN1/E1 since these reactions tend to occur in polar protic solvents, which stabilize the resulting carbocation better than polar aprotic solvents.]

Question 4: Is heat being applied to the reaction?

Quick N Dirty Rule #6: Heat favors elimination reactions.[This only becomes an important rule to apply when carbocation formation is indicated and we are trying to decide whether SN1 or E1 will dominate. At low temperatures SN1 products tend to dominate over E1 products; at higher temperatures, E1 products become more prominent.]

Deciding SN1/SN2/E1/E2 (2) The Nucleophile/Base

byJAMES

inALKYL HALIDES,ORGANIC CHEMISTRY 1

Last timeI talked about the process of deciding if a reaction goes through SN1, SN2, E1, or E2 as asking a series of questions. I call itThe Quick N Dirty Guide To SN1/SN2/E1/E2.This is the second instalment.

Once weve looked at a reaction and recognized that it has thepotentialfor proceeding through SN1/SN2/E1/E2 that is, is it an alkyl halide, alkyl sulfonate (abbreviated as OTs or OMs) or alcohol and asked whether the carbon attached to the leaving group is primary, secondary, or tertiary, we next can look at thereagentfor the reaction.

In substitution reactions, anucleophileforms a new bond to carbon, and a bond between the carbon and theleaving group is broken. In elimination reactions, abaseforms a new bond with a proton from the carbon, the C-H bond breaks, a C-C bond forms, and a bond between carbon and leaving group is broken.

Theres a lot of confusion from students on this point. How do I know whats a nucleophile and whats a base?.

Whether something is a nucleophile or a basedepends on the type of bond it is forming in the reaction.Take a species like NaOH. Its both a strong base and a good nucleophile. When its forming a bond to hydrogen (in an elimination reaction, for instance), we say itsacting as a base.Similarly, when its forming a bond to carbon (as in a substitution reaction) we say itsacting as a nucleophile.

In other words, its a relationship. For instance, when Im interacting with my wife, Im interacting with her as a husband. When Im talking to my mom, Im interacting with her as a son. Im the same person, but depending on whom Im interacting with, our relationship has different names.

Anyway. All this is prelude to making the key determination for today, which is:

1. Chargedbases/nucleophiles will tend to perform SN2/E2 reactions.

2. Reactions whereneutralbases/nucleophiles are involved tend to go through carbocations (i.e. they tend to be SN1/E1).

Again:Quick N Dirtyis an 80/20 set of principles. There are exceptions!!! But this framework will help us in most situations.

Charged Nucleophiles/Bases

Lets talk about charged nucleophiles first. Its important to be able to recognize charged nucleophiles. The charges are often not written in, but implied. For example, NaOEt (sodium ethoxide) actually has an ionic bond between Na(+) and (-)OEt, even though the charges themselves arent written in (us chemists are lazy that way). So if you see Na, K, or Li, for instance, youre looking at a charged nucleophile/base. Whether its K, Na, or Li doesnt matter for our purposes these are just spectator ions.

In both the SN2 and E2 pathways the reaction is concerted that is, the nucleophile/base forms a bond as the C-LG bond is broken. Since there is significant bond-breaking occurring in the transition state, the energy barrier for this step is higher than in the case of the E1 or SN1; were going to require a stronger nucleophile/base to perform these reactions. Recall thatthe conjugate base is always a stronger nucleophile.Negatively charged species have a higher electron density and are more reactive than their neutral counterparts.

Quick N Dirty Rule #3: If you see a charged nucleophile/base, you can rule out carbocation formation (i.e. rule out SN1/E1). In other words, the reaction will be SN2/E2.

We can break things down even more, depending on how strong a base the charged species is; go to the section at the bottom of this post for some examples where we can use base strength to rule out E2.

Reactions of Neutral Bases/Nucleophiles

Neutral bases/nucleophiles tend to be weaker than negatively charged bases/nucleophiles. In order for them to participate in substitution or elimination reactions, generally the leaving group must depart first, giving a carbocation.

Quick N Dirty Rule #4:If you dont see a charged species present, youre likely looking at a reaction that will go through a carbocation (i.e. an SN1 or E1).

One special case worth noting is if you see a strong acid such as H2SO4 or HCl with an alcohol as a substrate. Unless youre looking at a primary alcohol (where carbocations are very unstable) the reactions in these cases will almost always proceed through carbocations.

Its not uncommon to see a neutral nucleophile in the presence of a charged one (see example 2, below). In that case its likely acting as thesolvent.Well talk about solvents next.

Heres a chart where we evaluate this second question for deciding if a reaction is SN1, SN2, E1, or E2 (below).

Whats the biggest weakness of the Quick N Dirty approach? Its an oversimplification. To conclude that a reaction proceeds SN2 or proceeds E2 might give the impression that it gives 100% SN2 or 100% E2, and that is surely not the case! Often, these reactions compete with each other, and can therefore givemixtures products.When I say SN2 , for instance, I meanmostly SN2.There are likely other products in there.

The key lesson here is to understand the concepts what conditions favor each reaction? and then to be able toapplythe rules you know about each reaction to draw the proper product.

Next Post:The Role of Solvent

END QUICK N DIRTY GUIDE TO SN1/SN2/E1/E2 PART 2

Elaboration: Good Nucleophiles That Are Weak Bases

Some charged nucleophiles are actually poor bases. Heres a good rule of thumb: if the conjugate acid of the base/nucleophile is less than 12, an E2 reaction will be extremely unlikely. So if you see a nucleophile like NaCl, NaBr, KCN, and so on, it will favor SN2 over E2.

In contrast, the bulky base below (tert-butoxide ion) is a strong base but a poor nucleophile due to its great steric hindrance, so an E2 reaction is much more likely than SN2.

Exception: Neutral Nucleophiles in SN2 and E2 Reactions

One class of neutral nucleophiles/bases that readily perform E2 reactions (and SN2) are amines. For example, the tertiary alkyl halide below will undergo elimination through E2 here, although the Quick N Dirty rules call for SN1/E1. Amines are generally not the most useful nucleophiles for doing SN2 however because they lead to over-alkylation and ammonium salt formation. Finally, there are also neutral species which are good nucleophiles (and poor bases) such as PPh3, below.

Exception: Charged Nucleophiles In SN1 Reactions

Its also possible to use charged nucleophiles in SN1 reactions under certain conditions. If you have, for instance a tertiary alkyl halide in the presence of a high concentration of a good nucleophile (but weak base) such as those above, the carbocation that forms can be intercepted by that nucleophile. For example:

Here, the good nucleophile (cyanide ion), if present in large excess, can overpower the weak nucleophile (solvent). Of course the ultimate artiber of such statements are actual experiments.