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– The Substrate
Deciding SN1/SN2/E1/E2: The Key Role Of The Alkyl Halide (“Substrate”)
Having gone through the SN1, the SN2, the E1, and the E2 reactions in turn, we can now say the
following:
In this post and the next few, we’ll walk through one way of thinking about how to evaluate
whether a reaction will proceed through SN1/SN2/E1/E2. It’s not 100% foolproof*, but it’s a
decent enough framework for our purposes. Think of it as a set of 80/20 guidelines. I call it this:
Before getting specific with each of those 4 questions, let’s start with the most important
question you can ask in any situation like the ones above.
The most important step in evaluating any reaction is first to ask yourself “what type of
functional group(s) are present in this molecule? This is because the type of functional group
will dictate the type of reaction(s) that can occur. Note that in the questions above, all of the
starting materials are alkyl halides or alcohols. Substitution/elimination reactions are possible
for these substrates; many other reaction types (addition, for example) are not.
Given what we know about SN1, SN2, E1, and E2 reactions, we can say the following:
The “big barrier” to the SN2 reaction is steric hindrance. The rate of SN2 reactions
goes primary > secondary > tertiary
The “big barrier” to the SN1 and E1 reactions is carbocation stability. The rate of
SN1 and E1 reactions proceeds in the order tertiary > secondary > primary.
The E2 reaction has no “big barrier”, per se (although later we will have to worry
about the stereochemistry)
So how can we apply what we know about each of these reactions to simplify our decision?
As you can see, based on the information we’ve evaluated so far, we can’t make a definitive
decision on SN1/SN2/E1/E2. We’ll have to look at some other factors before we can make a
final decision. Next, we’ll evaluate the role of the nucleophile/base.
Why are alkenyl and alkynyl halides so bad? Well, the SN1, SN2, and E1 mechanisms all
involve considerable build-up of positive charge on the carbon bearing the leaving group, and the
stability of sp2 and sp hybridized carbocations is much lower than that for sp3 hybridized
carbocations [for the same reason that sp and sp2 anions are more stable than sp3 carbanions!].
E2 reactions are also more difficult due to the stronger C-H bonds of alkenes. [We’ll see later
that there is one example of an E2 that can occur on alkenyl halides, but the point remains that
they are very rare!]
* One question that comes up a lot is this: are there exceptions? Keeping in mind the two themes
of “steric hindrance” and “carbocation stability”, there are edge cases where we can have a
particularly sterically hindered primary alkyl halide, or a particularly stable primary carbocation.
For instance, the alkyl halide below (“neopentyl bromide”) is indeed primary, but is so crowded
on the carbon adjacent to the primary alkyl halide that it is essentially inert in SN2 reactions. On
the SN1/E1 side, the allyl halide below, while primary, can undergo SN1/E1 reactions because
the resulting carbocation is stabilized through resonance. As long as you keep in mind the “big
barriers” for each reaction, you should be fine.
Deciding SN1/SN2/E1/E2 (2)
– The Nucleophile/Base
SN1/SN2/E1/E2 Decision: The Role of the Nucleophile
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 instalment.
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 broken.
There’s a lot of confusion from students on this point. “How do I know what’s a nucleophile and
what’s a base?”.
It’s a relationship, in other words. 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:
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 (second) step 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 neutral counterparts.
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 (below).
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.
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.
(This is a more rigorous way of saying that weak bases don’t perform E2 reactions).
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.
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. [See: Alkylation of Amines (Sucks!)]
Finally, there are also neutral species which are good nucleophiles (and poor bases) such as PPh3,
below.
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 example:
Here, the good nucleophile (cyanide ion), if present in large excess, can overpower the weak
nucleophile (solvent). Of course the ultimate arbiter of such statements are actual experiments.
Recall that there are two important types of solvents to consider: polar protic solvents and polar
aprotic solvents. [See: All About Solvents]
Polar protic solvents are capable of hydrogen bonding. Recall that hydrogen bonding occurs
where we have a highly electronegative atom such as O or N directly bonded to hydrogen:
Let’s go back to the examples we were looking at in the first two posts.
Practically, you’ll only need to consider the solvent in an SN1/SN2/E1/E2 decision when
you’ve already analyzed the substrate and the nucleophile/base.
This is usually the case when you have a secondary alkyl halide with a strongly basic
nucleophile such as NaOCH3 or NaOH.
That’s especially the case in example #2, where we really can’t make the call as to whether it’s
SN2 or E2 until we’ve looked at the solvent. The fact that we are using a polar protic solvent
(EtOH) is the crucial piece of information that clinches the reaction as E2.
In the last post in this series we’ll look at the impact of temperature on these reactions.
Next Post: The Role Of Temperature
[Edit Dec 13]: What’s the weakness of the Quick N’ Dirty approach? Well, it doesn’t really
capture the true situation in these reactions, that is, that they don’t always give one product
exclusively. So keep in mind that when the Quick N’ Dirty approach says that E2 is the major
product, you may also have a small amount of competing SN2 occurring as well, or if SN1 is
favored, you might have small amounts of other reaction products also. The key points of this
exercise is to 1) remember the major factors that affect each type of reaction, and 2) once you
know the type of reaction, be able to apply it.
Deciding SN1/SN2/E1/E2 (4)
– The Temperature
The Quick N’ Dirty Guide To Determining SN1/SN2/E1/E2, Part 4 : The Role of
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?
(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!)
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 products].
This is truly a Quick N’ Dirty rule. It is not applied evenly and there are plenty of exceptions.
Your mileage will vary widely. I wish I had a hard, concrete example to show you that clearly
demonstrates the relationship between increased heat and a greater proportion of elimination
(E1) versus substitution (SN1) products. Sadly, I cannot find a good example at this time. So a
hand-wavy “elimination increases as heat is applied” will have to do for now.*
In the next post we’ll summarize all the Quick N’ Dirty Rules for determining whether a reaction
goes SN1/SN2/E1/E2.
Notes
* I am annoyed by the lack of hard data available when making pronouncements about the
SN1/SN2/E1/E2 decision. Wohler’s quote about the “monstrous and boundless thicket… into
which one may well dread to enter” seems appropriate here. I would love to see the control
experiments with various substrates run under identical sets of conditions that clearly delineate
the impact of each variable. I have not seen this. Any undergraduate labs out there with a desire
for performing this valuable public service?
A final note/editorial.
The post above is not so much about understanding some facet of organic chemistry as it is about
how to answer some arbitrary question from a textbook or exam. For the purpose
of understanding organic chemistry, it’s enough to know that heat favors elimination reactions.
For the purpose of knowing how to answer a particular kind of question on an exam, it will of
course depend on the examiner. There are wide variations. However, I will share with you one
common observation that I’ve seen in 2.5 years of seeing exams from all over the country.
First, background. In the laboratory, it is extremely common to heat reactions to get them to go
at a reasonable speed, such as in this example [from March’s Advanced Organic Chemistry 5th
ed; Cooper, K.A. et. al. J. Chem. Soc. 1948, 2038:]
However, on an exam, instructors – for various reasons, including a well-intentioned desire not
to overwhelm the student – will often omit some of the data. For exam purposes, if the above
reaction were written as a question it will often look like this:
Note how “heat” has been omitted, which is in accord with the principle of least effort. The
expected answer in this instance would be t-BuOH, the product of an SN1 reaction. Depending
on the question wording, some instructors will also insist that the E1 product be drawn as well.
Here’s the observation I see in many (but certainly not all) courses. If the word “heat” is
written in the exam question, it is often a clue from the instructor that an elimination is to
take place. In the following reaction, for example, the question would point to elimination (2-
methyl propene) being the major product.
If you are a student and your goal is to answer a particular type of question on an exam
correctly, I advise you to double check this issue with your instructor and get their answer on it.
There is tremendous inconsistency in this practice nationwide.
Wrapup: The Quick N’
Dirty Guide To
SN1/SN2/E1/E2
The basic premise is this: given 15-20 minutes to describe the basic principles by which one
could figure out if a given reaction goes down one of these pathways, these are, in my opinion,
the key factors to consider.
Quick N’ Dirty rules, by their nature, do not cover exceptions. To learn about some of the
exceptions, I advise you to go back and read the individual posts [One Two Three Four].
Even further back, I urge you to understand the key concepts behind each reaction, such
as nucleophilicity, leaving group ability, carbocation stability, and the mechanism of each of
these reactions. [SN1] [SN2] [E1] [E2]
Finally, I will preface this by saying that the best way to learn and understand how these
reactions work is to do a lot of practice problems and pay particular attention to situations where
you get the wrong answer – they are instructive.
Here goes: