Download Notes on Substitutions and Eliminations

Organic Chemistry
Clark College
Notes on Substitutions and Eliminations
The ability to control the outcome of a chemical reaction is key to planning a successful organic
synthesis. Substitution and Elimination reactions cover a broad range of reactions, leading to an even
broader range of products. These two reaction classes are intimately connected, so learning to
separate the reactions becomes the real challenge. Here are some tips and pointers to help you
effectively use substitutions and eliminations in your syntheses.
There are four pieces of information that will help you control the reactions.
1. The substrate – this is the organic molecule that will be transformed by the substitution or
elimination. This is often an organic halide, but it is not limited to those. It is any organic
molecule with a group that can be removed; a molecule that has an sp3-hybridized carbon
attached to something more electronegative, creating a polar bond. You will need to recognize
whether that carbon is 1°, 2°, 3°, or near any group that may lend electron density.
2. The leaving group – this is the group (halide or otherwise) that will be removed from the main
carbon substrate. The best leaving groups are very weak bases once they are free in solution.
Weak bases are anions that can readily accept negative charge, the charge is either far from
the nucleus (large ions) or is delocalized through resonance. For example, I-, Br-, and Cl- are all
weak bases, as the corresponding acids are strong. H-F is a weak acid, so F- is a stronger
base and is not as good as a leaving group.
3. The nucleophile – this is the Lewis Base that goes after the substrate, either to replace the
leaving group in a substitution reaction or that removes a proton to create a double bond in an
elimination reaction. Any Lewis base can be a nucleophile, the group simply needs a lone pair
of electrons that can be donated. Better nucleophiles are stronger bases, typically anionic.
Solvent choice effects nucleophilicity.
4. The solvent – since the molecules involved are inherently polar, the solvents must be polar to
dissolve all of the reagents. Some reactions are enhanced by protic solvents, those with an
acidic proton such as alcohols and water; whereas others are hampered by the acidic proton
and thus require aprotic solvents. Some good aprotic solvents are ethers, acetone, DMSO and
DMF.
By choosing the correct combination of the 4 reagents listed, we should be able to control and predict
the outcomes of the reaction. Let’s go through some of these choices, based on reaction type.
Substitutions
Factors favoring SN2 reactions:
1. The substrate – reaction is fastest for 1° or small, linear, unbranched 2° substrates. Because
inversion occurs at the site of nucleophilic attack, heavier groups (bigger than H) slow this
process down.
2. The leaving group – a good leaving group is always good, but not necessary for this reaction as
it follows a concerted mechanism – the nucleophile ‘pushes’ the leaving group out.
3. The nucleophile – This reaction depends on a strong nucleophile. Choose an anionic
nucleophile, not a neutral one, eg sodium salts, OH- instead of H2O.
4. The solvent – protic solvents hydrogen-bond with the nucleophile, lowering the reactivity. An
aprotic solvent is the best choice.
Factors favoring SN1 reactions:
1. The substrate – This reaction proceeds by forming a planar, sp2-hybridized carbocation.
Therefore, a branched 2° or 3° subtrate is preferred. This substrate has more groups that can
stabilize the carbocation through hyperconjugation, and the planar intermediate can reduce
Substitutions and Eliminations
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Organic Chemistry
Clark College
steric strain by separating the remaining groups in space. Also, carbocations that can be
resonance delocalized through double bonds also favor the SN1 reaction.
2. The leaving group – there must be a good leaving group for the reaction to begin. Halogens
and protonated alcohols are very good leaving groups, as halide ions and water are weak
bases.
3. The nucleophile – the nucleophile has no bearing on this reaction, so the reaction can tolerate
weak, neutral nucleophiles such as water and alcohols.
4. The solvent – A protic solvent can hydrogen-bond with the leaving group, helping to pull the
leaving group off of the substrate.
Eliminations
Factors favoring E2 reactions:
1. The substrate – This reaction can occur with any substrate. The reaction requires a hydrogen
on the neighboring carbon, and that the leaving group and eliminated H are 180° apart from
each other (anti-periplanar).
2. The leaving group – like the SN2 reaction, this does not rely on an exceptional leaving group.
3. The base – A strong base is needed to start the reaction. This can be accomplished with a
base such as OH- or OR- (a deprotonated alcohol) and will result in the more-substituted alkene
product. However, these bases are also strong nucleophiles, so small substrates also show a
substitution side product. To prevent the substitution, a non-nucleophilic, sterically-hindered
base, such as LDA or potassium t-butoxide is used. These bases will give only the lesssubstituted alkene product.
4. The solvent – a protic solvent will react with the base, so use an aprotic solvent.
Factors favoring E1 reactions:
The E1 reaction begins in the exact same fashion as the SN1 reaction, and cannot be separated from it!
The same factors that favor the SN1 reaction also favor the E1.
Some examples:
NaOH
DMSO
Br
OH
major
Br
LDA
Doing the same reaction with LDA gives the E2 product only.
CH3OH
Br
minor
SN2 reaction, with a 1° substrate, and a
strong, anionic nucleophile. The
nucleophile is also a strong base, so a
small amount of E2 product is formed.
H3CO
With a 3° substrate, and under solvolysis
conditions, where the nucleophile is also the
solvent, both SN1 and E1 products are formed
with roughly equal probability.
NaOH
Br
LDA
Br
Substitutions and Eliminations
Changing to a strong base changes the reaction to an E2 only.
Using a small base leads to the more substituted alkene. Using
a large, sterically hindered base favors the less substituted
alkene. Both reactions are done in polar, aprotic solvents.
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