Today starts a new series of posts on walking through one of the key classes of reaction in organic
chemistry: substitution reactions.
The goal of this series is to teach you:
How to recognize substitution reactions when they are presented to you
What the key components of a substitution reaction are (substrate, nucleophile, and leaving group)
– and how they influence whether or not a given substitution reaction will occur
The two main pathways for substitution reactions – the SN1 and SN2 mechanisms – and under
what conditions they operate
The role of solvent in substitution reactions, and how it affects reactivity
The role of stereochemistry in substitution reactions.
How to predict if a substitution reaction will proceed through an SN1 or SN2 pathway, given a
starting material and a set of conditions.
Substitution reactions are among the most versatile and important reactions in all of organic chemistry.
Below are drawn three examples of these reactions.*
Don’t understand the reactions below. Just focus on being able to see one thing: what bonds are formed
and what bonds are broken.
Just that one thing. Later on we’ll go into more detail about why things happen. But not today.
Here are three examples of nucleophilic substitution reactions.
What’s the pattern? In each case, we’re breaking a bond at carbon, and forming a new bond at
carbon. (and yes, salts form too… but this is organic chemistry, so we’re carbo-centric.)
This is an extremely common pattern for reactions and you will see it over and over again in Org 1 and
Now let’s set the stage for later discussion. Here’s some interesting results that experiments tell us. We
don’t get this information by thinking about what happens and predicting – we have to interrogate nature in
order to get her to give up her secrets.
Interesting observation #1: when we measure the reaction rate. In some substitution reactions the rate is
proportional to the concentration of two different species (e.g. the alcohol and HBr). In other cases, it
only depends on the concentration of one species (i.e. the alcohol). Interesting!
Interesting observation #2: In certain cases (like the reaction below) the reaction rate depends on
the type of alkyl halide. Primary alkyl halides are slow, but tertiary alkyl halides are fast.
Interesting observation #3: In other cases, the reaction rate depends on the type of alkyl halide, but it is
the primary alkyl halide that is fast. And the tertiary alkyl halide does not even give substitution products…
you’ll notice the double bond there. This is actually an elimination reaction.
Interesting observation #4: Finally, there is a property that *some* molecules have of rotating plane
polarized light. It’s been known since the late 19th century. In some substitution reactions, molecules that
are “optically active” retain their optical activity in the reaction… but in others, this “optical activity”
What’s going on? How can we come up with a hypothesis for why and how these reactions work?
Assuming no background knowledge except a understanding acid base reactions and a knowledge of
how to see hidden hydrogens, look closely: what bonds are formed and broken in each case?
In each case we’re breaking a bond at carbon and forming a new bond at carbon. In other words the
carbon has swapped partners.
Let’s take the first reaction and ask the second key question when understanding a new reaction: where
are the electrons in our starting materials?
We have an electron rich species (the oxygen) forming a bond with an electron poor species (the carbon
attached to the Cl). Using relative electronegativities to understand reactivity, and knowing that opposite
charges attract, and that electrons flow from negative to positive, it’s easy to imagine an interaction
between these two atoms.
Third question: how do these electrons move, then?
Well, the oxygen went from negatively charged to neutral – from owning a pair of electrons to sharing a
pair of electrons with carbon. And the chlorine went from neutral to negatively charged – from sharing a
pair of electrons with carbon to owning a pair of electrons.
It’s too early to say conclusively how this reaction occurs at this point without further experimental results,
but any description of how the bonds form and break (the mechanism) will have to explain the timing for
the forming of the O-C bond and the breakage of the C-Br bond.
By the way, does this type of reaction remind you of anything you’ve seen before? It should, if only a little
bit. It’s kinda like an acid-base reaction, where we’re breaking and forming a new bond at hydrogen,
except we’re breaking and forming a bond on carbon instead.
Let’s look back at the 4 components of an acid base reaction. We had an electron-rich species (a base)
donating a pair of electrons to an electron-poor species (the hydrogen), which formed a conjugate acid
(base plus proton) and a conjugate base (the part kicked off when the acid lost the proton)
A different terminology has been developed to describe each of these components for a substitution
reaction, as opposed to acid base reactions.
In the substitution reaction, we have an electron-rich species (the oxygen) donating a pair of electrons to
an electron poor species (the carbon) which forms a new product (the alcohol) and a new base (the part
kicked off when the C-Br bond broke).
The nucleophile is the electron-rich species donating a pair of electrons to carbon.
The electrophile (or “substrate” or “alkyl halide” in this case) is the species accepting the pair of
The species formed is the product.
The new base that breaks off of the carbon is called the leaving group.
Putting it all together for this reaction:
Next time, let’s understand this new concept – “nucleophilicity” in more detail, and how it differs from
It’s all about electrons. Electrons rule everything in organic chemistry. As we’ll 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…
he’s going to play with his truck, he wants to show you the truck, he wants a cookie, he needs to go to the
bathroom, He’sGonnaPlayWithTheTruckAgain, HE’SGONNABREAKTHETRUCK,
A hyperactive child in a small room is going to be bouncing off the walls! Driving everyone crazy! It’s a
very unstable situation.
But… if you throw that child out in the backyard… he’s got plenty of room to run around… everyone’s
happy… everything is just more calm and under control that way. It’s 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
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. It’s 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 are four main components we 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 I’ll 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! You’ve just been hired as the newest doctor on Dr.
Gregory House’s crack team! (pretend they’re bringing the show back) 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’. It’s up to you to assess all the evidence to
come up with the brilliant diagnosis of the correct reaction pathway.
And that’s how the rest of the posts in this series are going to go. I’ll introduce all the major systems and
components. We’ll look at what evidence we can gather from the leaving group, the nucleophile, the
electrophile, and the solvent, and I’ll show you how to assess all the evidence as a whole to diagnose the
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 (SN1 and SN2) and elimination (E1 and E2)
mechanisms. I don’t have anything to add to these posts, so I won’t 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 you’re familiar with the four mechanisms, and we’ll pick up next time with
assessing the leaving group.
3 ½ Steps To Any Substitution Or Elimination Reaction. Step
(½): What is the nature of the leaving group? by @azmanam
If you haven’t looked through James’ fantastic posts over the four possible mechanisms
(SN1, SN2, E1, E2), be sure to go back and read them before today’s installment.
Our first (half) step is to assess 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
sp3 hybridized 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.
Let’s take a look at the following potential leaving groups. Let’s look at the ‘good’ leaving groups versus
the ‘bad’ leaving groups and see how electron density stability helps explain the ranking of these leaving
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 it’s 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
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 sp3 hybridized. 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 doesn’t 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 we’ll 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, we’ll discuss how
the nature of the nucleophile helps our chemical differential diagnosis. If it’s 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.
Let’s look at the ‘2’ mechanisms first: the SN2 and the E2. In these reactions, the nucleophile directly
attacks the electrophile to start out the mechanism. It either directly attacks the electrophilic carbon
atom or the β-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 the SN1 and E1, 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 doesn’t have the
inherent energy to directly attack, it must be a considerably weaker nucleophile compared to the ‘2’
So we can already say that ‘strong’ nucleophiles will be evidence for the ‘2’ mechanisms, and ‘weak’
nucleophiles will be evidence for the ‘1’ mechanisms. But it’s a bit more nuanced than that, because
sometimes the nucleophile attacks the electrophilic carbon, and sometimes it attacks the β-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? It’s 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
potassium tert-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 makes t-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. Br – and I– are all
pretty good nucleophiles, but pretty bad bases. Other molecules with a negative 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 a ‘weak’ nucleophile and base: neutral charges,
electron density spread over a large volume (say, through resonance), and very low conjugate acid
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, it’s 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. Let’s start a chart. We’ll fill in more
of this chart as we assess the electrophile and the solvent, but we’ll start with the nucleophile:
Strong nuc/strong base
Strong nuc/weak base
SN1, E1, E2
Weak nuc/strong base
SN1, SN2, E1
Weak nuc/weak base
Let’s answer one interesting question before we finish for the day: Why wouldn’t a strong nuc/weak base
be evidence for SN2 and E1? And why wouldn’t a weak nuc/strong base be evidence for S N1 and E2?
Because the 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 won’t give the electrophile enough time to form the carbocation. It doesn’t
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
still must assess all the evidence before we make a diagnosis. Do you remember the episode
of House where Dr. 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, we’ll 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 of othercarbon 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 β-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 don’t even have a β-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.
SN1, E1, E2
SN1, SN2, E1, E2
SN1, E1, E2
Note that the secondary electrophile is evidence for all possible mechanisms… it doesn’t 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 β-carbon atom. The β-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 E1 reactions. Always be on the lookout for resonance!
Step 3: What is the nature of the solvent?
You might think the solvent shouldn’t 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 it’s 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 we’re 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
should read his post before reading on. Since most SN and E reactions utilize polar reagents, we typically
don’t see nonpolar solvents for these reactions very often. So let’s 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 S N1 and E1 reactions.
Polar aprotic solvents, by contrast, can’t 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 S N2
A couple of notes about the evidence we gain from solvents. I don’t like to say that solvents are
evidence against any mechanism. It is often possible to carry out, for instance, an S N2 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
wasn’t 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 S N2 and E2 mechanism
with a strong nuc/strong base. In general, polar protic solvents favor elimination, while polar aprotic
solvents tend to favor substitution.
SN1, E1, E2
One final note that fits best here, even though it’s 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.
in OR GA NI C CH EMIS TRY 1 , OR GA NI C RE AC TI ON S
The Quick N’ Dirty Guide To Determining SN1/SN2/E1/E2, Part
In previous installations of the Quick N’ Dirty Guide, we’ve
examined the substrate, the base/nucleophile, and the solvent.
Today, we’ll address the final variable to consider: the temperature.
If you’ve been following so far, you may have noticed that by this
point we should be able to differentiate all cases where SN2 is
favored over E2 (and vice versa) but are still left with this dilemma:
when a carbocation is formed, how do we determine whether SN1
or E1 products are favored?
First of all, note that the first step of the SN1 and E1 reactions is the
same: loss of a leaving group to give a carbocation. Since both
of these reactions proceed via the same intermediate, in practice a
mixture of both SN1 and E1 products will be found whenever the
reaction proceeds through a carbocation [where possible]. Given
that, however, we would still like to have a rule of thumb that tells
us what type of product should be the major product in most cases.
Generally speaking, SN1 products tend to predominate over
E1 products at lower temperatures. However, recall
thatelimination reactions are favored by heat. In cases where
substitution reactions and elimination reactions are in competition
with each other, increasing the temperature tends to increase
the amount of elimination products produced.
Here is a representative example:
Loss of bromide ion from the substrate leads to the formation of a
tertiary carbocation [stable, hence no rearrangement]. At low
temperatures, the SN1 pathway (above) will dominate: attack at the
carbocation by CH3OH, followed by loss of proton to give the ether.
The bottom pathway – removal of hydrogen from the carbon
adjacent to the carbocation – will be minor at low temperature [note
the formation of the more substituted alkene here – Zaitsev’s rule in
action]. As temperature is increased, the amount of elimination
relative to substitution should gradually increase.
This leads to the following Quick N’ Dirty rule of thumb.
Quick N’ Dirty Rule #6: When carbocations are formed, at low
temperatures, the SN1 pathway will dominate over the E1 pathway.
At higher temperatures, more E1 products will be formed.
(Note: before applying these reaction patterns to the substrate,
make sure to examine the carbocation that is formed. If a more
stable carbocation can be formed through a hydride or alkyl shift,
do this rearrangement first!)
Let’s go back to the examples we’ve been working on.
The third case – addition of H2SO4 to a tertiary alcohol – is a case
where a carbocation is formed in the absence of a good nucleophile
[the negatively charged oxygen on the conjugate base, [HSO4(-)] is
stabilized through resonance, reducing its reactivity]. The fact that
heat is being applied helps to tip the balance even further toward
E1 being dominant over SN1.
In the fourth example we have a tertiary halide [which will form a
stable carbocation] in a polar protic solvent [will help to stabilize the
intermediate carbocation] and heat is not indicated. Therefore using
Quick N’ Dirty Rule #6, we can say that SN1 products will dominate.
[E1 products will form as well, but they will not be the major
That’s it! We now have all the evidence we need to determine the mechanism for our
substitution/elimination reactions. Next time, we’ll see how to pull it all together and start predicting some
Let’s review what we’ve learned so far. 1) Electrons don’t 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 we’ve been building over the last couple of posts.
Strong nuc/strong base
Strong nuc/weak base
Weak nuc/strong base
Weak nuc/weak base
SN1, E1, E2
SN1, SN2, E1
SN1, SN2, E1, E2
SN1, E1, E2
SN1, E1, E2
SN1, E1, E2
Now it’s just a matter of assessing the evidence from each piece of the reaction and making the
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 S N2, 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 β-proton must be anti-coplanar (this can sometimes be
best viewed in a Newman projection or chair structure), and will lead to a specific E or Z alkene depending
on the other groups on the electrophile. For the S N1 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 is not present, 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.]
(2) – The Nucleophile/Base
in ALKYL HALIDES , ORGANIC CHEMISTRY 1
Last time I talked about the process of deciding if a reaction goes through SN1, SN2, E1, or E2 as asking
a series of questions. I call it The Quick N’ Dirty Guide To SN1/SN2/E1/E2. This is the second
Once we’ve looked at a reaction and recognized that it has the potential for 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 the reagent for the reaction.
In substitution reactions, a nucleophile forms a new bond to carbon, and a bond between the carbon and
the leaving group is broken. In elimination reactions, a base forms a new bond with a proton from the
carbon, the C-H bond breaks, a C-C π bond forms, and a bond between carbon and leaving group is
There’s a lot of confusion from students on this point. “How do I know what’s a nucleophile and what’s a
Whether something is a nucleophile or a base depends on the type of bond it is forming in the
reaction. Take a species like NaOH. It’s both a strong base and a good nucleophile. When it’s forming a
bond to hydrogen (in an elimination reaction, for instance), we say it’s acting as a base. Similarly, when
it’s forming a bond to carbon (as in a substitution reaction) we say it’s acting as a nucleophile.
In other words, it’s a relationship. For instance, when I’m interacting with my wife, I’m interacting with her
as a husband. When I’m talking to my mom, I’m interacting with her as a son. I’m the same person, but
depending on whom I’m interacting with, our relationship has different names.
Anyway. All this is prelude to making the key determination for today, which is:
Charged bases/nucleophiles will tend to perform SN2/E2 reactions.
Reactions where neutral bases/nucleophiles are involved tend to go through carbocations (i.e.
they tend to be SN1/E1).
Again: Quick N’ Dirty is an 80/20 set of principles. There are exceptions!!! But this framework will help us
in most situations.
Let’s talk about charged nucleophiles first. It’s 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 aren’t written in (us chemists are
lazy that way). So if you see Na, K, or Li, for instance, you’re looking at a charged nucleophile/base.
Whether it’s K, Na, or Li doesn’t 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; we’re going to require a stronger
nucleophile/base to perform these reactions. Recall that the conjugate base is always a stronger
nucleophile. Negatively charged species have a higher electron density and are more reactive than their
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 don’t see a charged species present, you’re 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 you’re looking at a primary alcohol (where carbocations are very unstable) the reactions
in these cases will almost always proceed through carbocations.
It’s not uncommon to see a neutral nucleophile in the presence of a charged one (see example 2, below).
In that case it’s likely acting as the solvent. We’ll talk about solvents next.
Here’s a chart where we evaluate this second question for deciding if a reaction is SN1, SN2, E1, or E2
What’s the biggest weakness of the Quick N’ Dirty approach? It’s 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
give mixtures products. When I say “SN2″ , for instance, I mean mostly 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 to apply the rules you know about each reaction to draw the proper product.
——–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. Here’s 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
It’s 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
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.