SUBSTITUTION AND ELIMINATION HANDOUT

SUBSTRATE

Remember that SN2 reactions are under steric control. The more sterically hindered the halogen bearing carbon of an alkyl halide is, the slower the rate of reaction.

(fastest) CH3-X > 1˚ R-X > 2˚ R-X > Neopentyl R-X > 3˚ R-X (slowest)

Remember that SN1 reactions are controlled by the stability of the carbocation intermediate formed. The greater the stability of the carbocation intermediate, the faster the rate of reaction. Remember that primary allylic and primary benzylic carbocations are between 3° and 2° carbocations in terms of stability. This is due to resonance stabilization of the carbocation intermediate. Stability of carbocation intermediates R R R H > ≈ > > CH2 > R R R H H H H H

3˚ Benzylic Allylic 2˚ 1˚ methyl

CH3-X (Methyl halides): May only react by SN2. This type of alkyl halide lacks beta hydrogens, and therefore are incapable of undergoing elimination reactions.

1˚ R-X (Primary alkyl halides): May react by either SN2 or E2.

SN2: Favors SN2 reactions under most conditions E2: High reaction temperatures and the use of a very large (sterically hindered) strong bases favors E2.

1° Allylic or Benzylic Alkyl Halides: May only react by either SN1 or SN2. This type of alkyl halide lacks beta hydrogens, and therefore are incapable of undergoing elimination reactions. Note E1 may be possible for the resonance structure!

Solvent will determine whether the reaction mechanism will be unimolecular (SN1) or bimolecular (SN2). Polar aprotic solvents favor SN2 while SN1 requires polar aprotic solvents.

2˚ R-X (All secondary alkyl halides): May react by either SN2,SN1, E1, or E2.

Solvent will determine whether the reaction mechanism will be unimolecular (SN1 or E1) Or bimolecular (SN2 or E2). Polar protic solvents favor SN1 and E1 while polar aprotic solvents require SN2 or E2. Note: a strong base will always favor E2!!!!

SN2: Weakly basic nucleophiles favor SN2. Reactions at room temperature (R.T.) favor SN2.

E2: Strong bases favor E2. Sterically hindered bases favor E2. High reaction temperatures favor E2.

SN1: Polar protic solvents favor SN1. Reactions at room temperature (R.T.) favor SN1. Will always be favored over E1.

E1: Polar protic solvents favor E1. E1 will always compete with SN1.

3˚ R-X (All tertiary alkyl halides): May react by SN1, E1, or E2. Note: E1 and SN1 always compete with one another.

SN1: Polar protic solvents favor SN1. Reactions at room temperature (R.T.) favor SN1. SN1 will always be favored over E1.

E1: Polar protic solvents favor E1.

E2: Strong bases always favor E2. Sterically hindered bases favor E2. High reaction temperatures favor E2.

SOLVENT:

There are three types of solvents: polar protic solvents, polar aprotic solvents, and non-polar solvents.

Non-polar solvents:

Non-polar solvents cannot solvate (dissolve) cations or anions. As a result, they are usually incapable of dissolving the ionic compounds (or other nucleophiles) typically used in either nucleophilic substitution or elimination reactions. Thus, this class of solvents is unfavorable for substitution and elimination reactions.

Examples of these solvents are hexane and benzene (Any hydrocarbon is non-polar).

Polar aprotic solvents:

This class of solvents can solvate cations AND NOT ANIONS. This is primarily due to the fact that these solvents contain oxygen atoms which can act as a Lewis base towards metal ions; however, they do not have hydrogen atoms bonded to highly electronegative elements (such as oxygen). Accordingly, these solvents may not form hydrogen bonds around the anions, and thus solvate them. Anions dissolved in this class of solvents are referred to as being “naked,” or free of the inhibitory solvent cage which retards their reactivity in substitution reactions. This class of solvents requires SN2 and E2 reactions.

Examples of this class of solvents are DMSO, DMF, HMPA, acetonitrile, acetone, etc. These solvents have dipole moments, but are not capable of forming hydrogen bonds. Polar protic solvents:

This class of solvents can solvate both cations and anions. They differ from polar aprotic solvents in that they have hydrogen atoms which are bonded to strongly electronegative atoms. Thus, these solvents may form hydrogen bonds around the anion, forming a solvent cage.

This class of solvents favors SN1 and E1 reactions. It is important to note that SN2 and E2 reactions may occur in this type of solvent. E2 will usually be favored when you have a very strong base. SN2 will usually be favored when your substrate is a methyl or 1° alkyl halide (excluding allylic or benzylic, which would prefer to react via SN1 under these conditions).

Examples of this class of solvents are EtOH, any alcohol, any carboxylic acid, and H2O.

NUCLEOPHILES:

Remember that all nucleophiles are bases and all bases are nucleophiles.

Note: Nucleophiles which are neutral (uncharged molecules, exe. H2O) are weaker than nucleophiles which are negatively charged (anions, exe. H-O-). Anions have an abundance of electrons and want to become neutral, while neutral nucleophiles become ionic intermediates upon substitution.

+ - Exe: H2O + CH3-I → H2O-CH3 +I Weaker nucleophile neutral charged vs. - - F + CH3-I → F-CH3 +I Stronger nucleophile charged neutral

As a general rule, the larger the nucleophilic atom, the greater it’s reactivity in substitution reactions. This comparison is only valid when comparing ions in the same group of the Periodic Table. Remember that this effect may be dependent upon solvent (especially the halogens). Exe:

PH3 is a better nucleophile than NH3 H-S- is a better nucleophile than H-O- I- is a better nucleophile than F-

When comparing Nuc with the same Nuc atom, the stronger base will be the better nucleophile.

Exe: - - - (Strong Nuc) R-O > H-O > RCO2 > R-O-H > H2O (Weak Nuc) pKa of conj. acid: ~16 15.7 ~4-5 ~ -1 ~ -2

Remember that SN1 reactions are insensitive to nucleophile strength.

LEAVING GROUP

For all intensive purposes, there are only three types of leaving groups you need to concern yourself with: halogens, sulfonates and small neutral molecules. In general, the more stable the anion, the better the leaving group. Leaving group ability is opposite the basicity of the ions/molecules in question.

Halogens:

(Best L.G.) I- > Br- > Cl- > F- (Worst L.G.) (Strongest acid) (Weakest acid) (Weakest base) (Strongest base)

Sulfonates:

The tosylate ion is a slightly better leaving group than iodide and it is a much better leaving group than bromide. Also note that other sulfonates exist and they are also excellent leaving - - - - groups (Methane sulfonate = MsO = CH3SO3 ; trifluoromethane sulfonate = TfO = CF3SO3 ; - - benzene sulfonate = PhSO3 = C6H5SO3 )

O S O- O Tosylate ion TsO-

Small neutral molecules:

Water molecules (and occasionally alcohols, ROH) are excellent leaving groups in reactions that are performed under highly acidic conditions. Water is an excellent leaving group because it is neutral.

Thus, the overall leaving group ability follows this trend.

- - - - - (Best L.G.) TfO > TsO > I > Br > Cl > H2O (Worst L.G.)