CHEM2021 Learning Objectives

Organic Chemistry • Recognise the interconnected nature of substitution

and elimination processes.
Stereochemistry and Mechanism • Be able to indicate which process might occur given
Part 5 - Substitution vs Elimination: A comparison the reagents and conditions.
(Section 9.8, but also basics covered earlier)
• Indicate how these might be experimentally verified.

Dr Jason Harper
Dalton 223, x54692
j.harper@unsw.edu.au

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Nucleophile vs base So what favours an E2 mechanism

Both nucleophiles and bases are electron rich - generally • A high concentration of a strong base.
nucleophiles are bases and vice versa. • A readily accessible H atom.
An example we’ve already seen is ... • A polar aprotic solvent.
O O

OH
OH

HO H H2 O

Given this, let’s remind ourselves of four slides from

previously. 213 214
So what favours an SN2 mechanism So what favours an E1 mechanism
• Ready access to the antibonding orbital of the C-X. • A weak base.
• A polar aprotic solvent. • A stable carbocation intermediate - so a more
substituted alkyl halide.
• A polar protic solvent.

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So what favours an SN1 mechanism Things you’ve always wanted to know

• A stable carbocation intermediate - so a more So this leaves the question ...
substituted alkyl halide.
• A polar protic solvent. Given a compound with a leaving group is treated
with a nucleophile/base, how do you know what
reaction happens and by what mechanism?

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 Before we start Step 1 - Look at the electrophile
Many people get confused when considering these reactions The best place to start - it divides into categories easily
and consider that and the structures markedly affect reaction outcome.
‘only one mechanism can be operating’
Easy one to start - methyl systems because they can’t
Actually no - all mechanisms are likely to be happening to
some extent (even if a very, very, very small extent). undergo elimination reactions (no !-H).

What we are talking about here is competition and it really is X

H
H
quite common to get mixtures of products. H H Nu X
H H HH
H

So let’s look at how each component of a reaction might affect

the rate (and hence competitiveness of each mechanism). SN1 - very unlikely SN2 - very likely
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Step 1 - Look at the electrophile Step 1 - Look at the electrophile

Primary systems are slightly trickier because we have to With the SN2 case, it is important to consider the
consider all four options - though two are the same! substitution at the methyl, as it can differ markedly.

X H3C
H X
E1/SN1 - unlikely H3C H3C Unhindered - more likely Nu
H H HH
H

CH3
H H H3C CH
E2 - likely Base Hindered - less likely
Nu X
H X HH
H H

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Step 1 - Look at the electrophile Step 1 - Look at the electrophile
Moving on to secondary systems. And finally tertiary

X X
H CH3
E1/SN1 - possible H3C H3C E1/SN1 - very likely H3C H3C
CH CH3 CH CH3
H 3 CH3 3

H3C H3C
SN2 - possible Nu X SN2 - unlikely Nu X
H3CH H3C CH
3

H CH3 H3C CH3

Base Base
E2 - possible H X E2 - very likely H X

H H 223 H H 224

Remember it is a competition ... So that leaves this table ...

Methyl SN2
Primary (unhindered) SN2, E2
Primary (hindered) SN2, E2
Secondary SN2, E2, SN1, E1
Tertiary E2, SN1, E1

... which clearly needs to be further amended.

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What next ? - the base/nucleophile Step 2 - Look at the Nu/B
The next thing to do is to recognise that base strength To start with recognise that they are not involved in the
and nucleophile strength don’t always correlate. rate determining step for E1/SN1 processes. Hence no
effect of the Nu/B.
1. Powerful nucleophiles are also typically strong bases, X
(like ethoxide, etc.)

2. A strong base is not necessarily a strong nucleophile. It is only when the Nu/B is involved in the rate
Why? It is usually to do with hindrance - it can’t get in. determining step that changing it has an effect.
Base
Nu X H X
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Step 2 - Look at the Nu/B Step 2 - Look at the Nu/B

Strongly basic and unhindered nucleophiles are systems Strongly basic and but sterically hindered nucleophiles
such as linear alkoxides. are systems such as t-alkoxides.

Readily react via both SN2 and E2 mechanisms. The

H3C N N
amount of each is very dependent on conditions later. O
H3C CH N N
3
Base
Nu X H X t-BuO- DBU DBN

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 Step 2 - Look at the Nu/B Step 2 - Look at the Nu/B
Weakly basic but charged nucleophiles are systems such
H3C as acetate and charged sulfur nucleophiles.
An E2 process occurs readily. O
H X H3C
H3C CH
3 An E2 process occurs O
X
O H
(but comparatively slowly)
An SN2 process can be slow - the nucleophile just can’t
get in! An SN2 process proceeds readily*
H3C
O X H3C
H3C CH O X
3
O
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Step 2 - Look at the Nu/B Step 2 - Look at the Nu/B

Uncharged species such as water and alcohols tend to be Note that when we consider the same substrate groups
very poor at both E2 and SN2 processes. we need focus on those where competition is likely.

Remembering that we are talking about competition Why?

here, the result is that the E1 and SN1 processes A methyl halide (for example) will always under
dominate in these situations. substitution through a bimolecular process, irrespective
of the Nu/B. It might be really, really slow (think about
where useful to know) but it is the only option.
H
Nu X
HH
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 Our table is now more complicated... Step 3 - Look at conditions
Weakly Strong Strong There is actually a marked difference in the degree of
Substrate Poor Nu
basic Nu unhindered Nu hindered Nu substitution vs elimination depending on the temperature.
Methyl SN2* SN 2 SN 2 SN 2
Primary
Why? It really is all about entropy and whether there is
SN2,* E2* SN 2 SN 2 SN2, E2 an increase in the transition state.
(unhindered)
Primary
SN2,* E2* SN 2 E2, SN2 E2 Remember, the free energy change of a system is related
(hindered)
to both the enthalpy change and entropy change.
Secondary SN1,* E1* SN 2 E2, SN2 E2

Tertiary SN1, E1 SN1, E1 E2 E2 "G = "H - T"S

... but virtually complete - need to consider SN2 vs E2. 236

Step 3 - Look at conditions Step 3 - Look at conditions

Now in this case, we are talking about activation Guessing activation parameters is not always easy from
energies. The smaller the activation energy, the faster transition states - here especially. It helps if you consider
the reaction rate. the products
!
"G‡ = "H‡ - T"S‡ Base Base H
BaseH X-
H X X
!

So for a smaller "G‡ (which is always positive), you

need a greater (less negative) "S‡.
! !
Nu X Nu X Nu X

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 Step 3 - Look at conditions Some notes to finish before examples
As such, the entropy change on going to the transition • Remember, it is always a competition. The above
state in the E2 case is less negative. arguments give you the most likely product, not the only
product.
This means that increasing the temperature lowers the
free energy of activation for E2 relative to SN2. • For a given electrophile and nucleophile/base,
changing the solvent and temperature can adjust this.
So heating favours E2!
• Product isolation gives you the major product, but it is
changing the concentration of nucleophile/base or
considering stereochemistry that confirms mechanism.
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Some examples Some examples

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 Some examples An example - from my lab

Cl O Me

MeOH

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A demonstration of why you care. A demonstration of why you care.

The classic example of this is For any given ether, there are two possible ways to make
Williamson Ether Synthesis it using this method.
O
R R'

R O R' Br R Br R' O

The alkoxide is typically produced from the Often one of the ‘forward’ equivalent reactions works
corresponding alcohol using NaH or Na. well while the other doesn’t.
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A demonstration of why you care. A demonstration of why you care.
Consider the example below - in making this ether you ‘Forward’/synthesis processes
could consider going from two bromide/alkoxide
combinations. O Br

O Br O

O Br
O
HO
Br O
OH
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What do you have to be able to do?

• Given a alkyl halide (or similar leaving group) and a
nucleophile/base, predict the outcome of the reaction under
the conditions given.
• Suggest ways that the mechanism could be confirmed.
• For a given product (particularly ethers) indicate an
appropriate way for them to be synthesised (based on
arguments above, including conditions).

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