Nucleophilic Substitution Reactions – Sn1 & Sn2 Stereochemistry

– Nuclephilic Substitution Reactions

The viability of nucleophilic substitution over a single bond is determined by the bond polarity. A nucleophile (Nu-) will attack the δ+ atom in a polar bond and replace the existing δ- atom.

A good example of this is the haloalkanes, where the halogens are more electronegative than the Carbon atom. As the the halogen has a higher affinity for -ve charge, the bonding electrons are found closer to the halogen than the carbon, shifting the dipole charges in the molecule.

Nuleophilic Substitution of Iodine with Cyanide in Iodomethane.

Nuleophilic Substitution of Iodine with Cyanide in Iodomethane

As you can see the nucleophile (which likes +ve charge) attacks the δ+ carbon atom, and this essentially severs the C-I bond, releasing I-.

There are a large number of other suitable nucleophiles, including the following. I’ve included products too, excuse the lack of correct punctuation. This allows conversion of an Alkyl Halide into many different compounds.

Starting Material Reacts With Produces AKA
RX PPh3 RP+Ph3X- Phophodium Salt
RX R’S- RSR’ Thioester
RX Na2S RSH Thiol
RX NC- RCN Nitrile
RX HCC- HCCR Alkyne
RX MeCOO-Ag+ MeCOOR Ester
RX EtO- ROEt Ether
RX HO- ROH Alcohol
RX N3- RN3 Alkyl Azide
RN3 H2 / PdC RNH2 Amide
RX NH3 RNH3+X- Ammonium Salt
RNH3+X- HO- RNH2 Amide

The ones in GREY at the bottom are the amide chain – there are two routes to an Amide. One is through an alkyl azide and the other through an ammonium salt.

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A special note: Hydride (H-) reducing agents such as LiAlH4 can be used as sources of nucleophilic hydride ions which will replace the halogen group. This allows conversion of an alkyl halide into an alkane.

Nucleophilic Substitution of Halide with Hydride via LiAlH4

Nucleophilic Substitution of Halide with Hydride via LiAlH4

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A stable molecule is a good leaving group, such that H2O is better than HO-. In haloalkanes, reactivity goes from RI > RF (travelling down the group).

This can be explained better when we look at the basicity and nucleophilicity of the atom/molecule. Note that while Nucleophilicity is a kinetic property determining the rate of reaction with a Carbon atom (how fast the reaction progresses), Basicity is a thermodynamic property determining an atom/ion/molecul’s ability to accept a proton.

Nucleophilicity (rate of reaction): NC- > I- > RO- > HP- > Br- > Cl- > ROH > H2O
Basicity (ability to accept proton): RO- > HO- > NC- > H2O > ROH > Cl- > Br- > I-

– The Reaction Pathway – Sn1 and Sn2 Reactions

There are two main pathways that a nucleophilic substitution reaction can follow:

Sn1 (Substitution, Nucleophilic, Unimolecular):

  • Substrate ionises to form a planar intermediate carbocation in the rate determining step.
  • The intermediate cation then rapidly reacts with the nucleophile. This means there are two transition states.
  • This is a 1st order reaction as rate = k[substrate]. It is a unimolecular process.
  • Favoured in polar solvents – this aids ionisation.
  • Favoured Tertiary > Secondary > Primary as the two state process allows access to the carbon centre without steric hindrance (see Sn2 below).
Sn1 Substitution

Sn1 Substitution

Sn1 creates a racemic product (an equal amount of left and right enantiomers) which as a result is optically inactive. This means it will not rotate polarised light.

Sn2 (Substitution, Nucleophilic, Bimolecular):

  • Reaction occurs completely within one transition state.
  • This is a second order reaction as rate = k[substrate][nucleophile]
  • Reaction favoured in polar aprotic solvents (solvents which have high polarity but cannot dissociate a H+) such as DMF (Dimethylformamide) and DMSO (Dimethyl Sulfoxide).
  • Steric hindrance slows or stops reaction progression in tertiary systems as steric crowding stops attack by the nucleophile (aka there isn’t room!) and tertiary cations are quite stable. In this case we would expect Sn1. Note that the “back route” must be clear else the reaction will proceed by Sn1.
  • Favoured Primary > Secondary > Tertiary.
Sn2 Substitution

Sn2 Substitution

Sn2 creates a product with an inverted stereo structure to that of the substrate. Essentially the Nucleophile attaches to the opposite side from the leaving group, inverting the molecule’s original stereochemistry.

– Alcohols

Alcohols are extremely important for synthesising new molecules:

Synthesising new molecules from Alcohols (In this case Propanol)

Synthesising new molecules from Alcohols (In this case Propanol)

It is especially useful when you consider that we can already use the Alkyl Halide table from above to form a variety of molecules that way.

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