Nucleophilic substitution

Question 1

Whats the definition of a nucleophile?

Give some examples of nucleophiles

Answer 1

a molecule or substance that has a tendancy to donate electrons or react at electron-poor sites such as protons

Examples attached

Question 2

Whats the definition of an electrophile

Give some examples

Answer 2

An electrophile is an atom or molecule that accepts an electron pair to make a covalent bond.

Examples attached

Question 3

What type of mechanism is each of the following…

1. Nucleophile adds first, then the leaving group departs
2. Leaving group departs first, then the nuclephile adds
3. Nucleophile arrives whilst the leaving group departs

Answer 3

1. Impossible
2. Possible SN1 mechanism
3. Possible SN2 mechanism

Question 4

Why is the following statement impossible:

Nucleophile adds first, then the leaving group departs?

Answer 4

Consider if the nucleophile adds first, then the leaving group departs. This is IMPOSSIBLE since an intermediate stage including pentavalent carbon (5 bonds so 10 bonding shell (shared) electrons) would be involved

Question 5

What mechanism is this and why?

Answer 5

This is a two-step mechanism:

Step 1: the leaving group departs (slow)

Step 2: the nucleophile arrives (fast)

The rate of reaction depends only on [PhCH2Cl] and the rate is NOT increased by increasing [nucleophile] so the step involving PhCH2Cl is rate determining= step 1

The rate determining step is unimolecular (electrophile only) so this mechanism is called SN1

Leaving group departure is the most important step (formation of carbocation)

Question 6

What mechanism is this and why?

Answer 6

This is a one-step mechanism:

The rate is dependent on both the [nucleophile] and the [electrophile]

The rate determining (only) step is bimolecular (electrophile and nucleophile) so this mechanism is called SN2

Question 7

Draw the electrophile structure of the following;

• methyl
• primary
• secondary
• tertiary

State what mechanism it can react by and why?

Answer 7

SN1 is favoured for electrophiles that for a stable carbocation intermediate (ones with more R groups)

Sn2 is favoured for electrophiles that have fewer ‘R-groups’ (less stable carbocations) since these hinder attack by the nucleophile= Steric hindrance

Question 8

Consider this SN2 mechanism, tell me what this means for the products/ configuration?

Answer 8

The nucleophile approaches the opposite side of the electrophile to the side where the leaving group is departing.

So, the stereochemistry of the tetrahedral carbon where substitution has occurred is inverted in the product.

This leads to an inversion of configuration for a chiral electrophile

Inversion doesn’t mean R and S is established

Question 9

Consider the SN1 reaction, what will this lead to in the products

Answer 9

It leads to a racemic mixture of products

Question 10

If a moleucule contains two possible sites for nucleophilic substitution, how can we predict at which site the reaction will occur?

Answer 10

• The stability of the anion product of the leaving group (i.e. carboxylate or bromide here) plays an important role in control of the rate of reaction
• (steric hindrance to nucleophilic attack in SN2 and carbocation stability in SN1 are also important factors, along with the specific reaction conditions used)
• Compare two reactions, in which the leaving group differs. Which is fastest?

The anion product is formed from the leaving group in the rate determining step of SN1 or SN2 reaction. So, the fastest reaction is the one in which the more stable anion (bromide or carboxylate) is formed

• Compare the stability of the two anions by comparing the acidity of HBr with CH3CO2H:
• Stronger acids have a lower pKa value (see lecture 4). So HBr is a stronger acid than CH3CO2H = HBr is more dissociated (equilibrium is more to the left) i.e. Br- is the more stable anion
• More acidic means a better leaving group

Question 11

Is OH a good or poor leaving group?

Answer 11

A poor leaving group (H2O is a weak acid with pKa=16)

Question 12

Is H2O a poor or good leaving group?

Answer 12

But H2O is a very good leaving group (H3O+ is a strong acid with pKa = -1.7) So nucleophilic substitution of alcohols requires protonation of oxygen to take place first

Question 13

WHen can a species show more resonance forms?

Answer 13

when a species is more stable (= less reactive)

Question 14

When is the nucleophile strength decreased?

Answer 14

If the nucleophilic lone pair can be shared by multiple electronegative atoms. this is called delocalisation

Question 15

What is more nucleophilic;

amines or alcohol?

Answer 15

amines are more nucleophilic than alcohols?

Question 16

Whats more electronegative, oxygen or nitrogen?

why?

Answer 16

oxygen is more electronegative than nitrogen

• Outer shell electrons more are held more tightly by oxygen than by nitrogen.
• This means that oxygen lone pair electrons are less available to participate in substitution reactions

Question 17

Tell me how nucleophile strength changes in a group?

Answer 17

• Outer-shell electrons that get involved in reactions are shielded from the positive nucleus by the inner shell electrons.
• As the elements get larger (i.e. heavier) there are more shielding electrons, so that the outer-shell electrons are more available to react.
• So, within a group of the periodic table, nucleophile strength increases as we go down the group

Question 18

Tell me how rate is effected in SN1 reactions by the following;

• Concentrations of nucleophiles
• Type of nucleophile
• Leaving group

Answer 18

Step 1 is the rate-determining step and involves only the electrophile PhCH2Cl.

The rate is not increased by increasing the concentration of the nucleophile CH3S- (the nucleophile is only involved in step 2).

The rate is not increased by changing to a better nucleophile.

The rate is dependent on how good the leaving group is (departs in step 1)

Question 19

Tell me how rate in an SN2 reactions is affected by the following

• concentration of nucleophile
• Type of nucleophile
• Leaving group

Answer 19

The rate is increased by increasing the concentration of nucleophile CH3S-

The rate is increased by changing to a better nucleophile.

The rate is dependent on how good the leaving group is (departs in the rate-determining step)

Question 20

Tell me if the following reactions are SN1 or SN2?

• Terpene biosynthesis
• Steroid and alkaloid biosynthesis
• methylation of DNA, RNA and proteins

Answer 20

Terpene biosynthesis: SN1

Steroid and alkaloid biosynthesis: SN2

Methylation of DNA, RNA and proteins: SN2

Question 21

Tell me about Biological methylation reactions and SN2?

Answer 21

Involves transfer of a methyl group (-CH3) from an electrophile donor to a nucleophile via SN2. The electrophile donor is usually S-adenosylmethionine (SAM)