SUBSTITUTION REACTIONS OF HALOALKANES

SN2 rate law

Rate = k[substrate][Nu]. 2nd order, bimolecular, one concerted step with no intermediate

SN2 mechanism

Backside attack. Bond making and breaking are simultaneous through a single transition state

SN2 stereochemistry

100% inversion at the electrophilic carbon (stereospecific). Other stereocenters are unaffected

SN2 substrate reactivity

methyl > 1° > 2° >> 3° (3° negligible). Branching at the alpha carbon causes steric hindrance

Leaving group ability

Weaker base = better LG (conjugate base of a strong acid). Cl- < Br- < I-. Sulfonates (OTs, OMs, triflate) are excellent. OH- is poor

Nucleophilicity trends

More negative > neutral (HO- > H2O, H2N- > NH3). Increases to the left in a period (H2N- > HO- > F-) and down a group

Steric effect on the nucleophile

Bulkier Nu = worse nucleophile, e.g. CH3O- > (CH3)3CO- and (CH3)2NH > [(CH3)2CH]2NH

Which sterics matter most in SN2?

Sterics around the electrophilic carbon (alpha carbon) are the most significant

Protic solvent effect on Nu

Solvent H-bonds to Nu- (ion-dipole shell), which impedes it. Small, charged Nu- are affected most

Nucleophilicity order in protic solvents

I- > Br- > Cl- > F-. F- is heavily solvated even though it is the most basic

Nucleophilicity order in aprotic solvents

Follows basicity: F- > Cl- > Br- > I- ("naked" anions)

Best solvents for SN2

Polar aprotic (DMSO, DMF, acetone, acetonitrile, HMPA). They dissolve salts without H-bonding, giving rate increases of about 10^6 vs methanol

Protic vs aprotic solvent

Protic has an acidic H (O-H, N-H) and can H-bond (H2O, ROH). Aprotic has no acidic H

SN1 rate law

Rate = k[substrate]. 1st order, unimolecular

SN1 rate-determining step

Step 1: leaving group departs to form the carbocation

SN1 steps with an anionic nucleophile

2 steps: (1) LG leaves to give a carbocation, (2) Nu attacks

SN1 steps with a neutral nucleophile

3 steps: (1) LG leaves, (2) Nu attacks to give an oxonium ion, (3) proton transfer to a base gives the neutral product

Solvolysis

SN1 where the solvent is the nucleophile (neutral, weak, polar protic). Hydrolysis = H2O, ethanolysis = EtOH, acidolysis = HCO2H

SN1 stereochemistry

Planar sp2 carbocation is attacked from either face, giving racemization (50:50 R/S, optically inactive)

Polar protic solvent effect on SN1

Stabilizes the polar transition state and the carbocation/ion pair, lowering the activation energy and speeding the reaction

SN1 substrate reactivity

3° > 2° >> 1° > methyl. Primary and methyl give no SN1

Carbocation stability

3° > 2° > 1° > methyl. Benzylic and allylic cations are also stabilized by resonance

Hyperconjugation

Donation of electron density from adjacent C-H or C-C sigma bonds into the empty p orbital. It is why more substituted cations are more stable

Carbocation rearrangement

1,2-hydride or methyl shift to form a more stable cation (2° to 3°). It can change the site of attack and give an unexpected product

When to watch for rearrangement

Any SN1/unimolecular reaction where a 2° cation sits next to a carbon with an H or methyl that would give a 3° cation

Tertiary alkyl halide mechanism

SN1 only (too hindered for SN2)

Primary alkyl halide mechanism

SN2 only (cannot stabilize a carbocation)

Secondary alkyl halide mechanism

Either SN1 or SN2, depending on solvent, leaving group, and nucleophile

Conditions that favor SN1

Very good LG, poor (neutral) nucleophile, polar protic solvent

Conditions that favor SN2

Reasonable LG, good (anionic) nucleophile, polar aprotic solvent

2-bromopropane + CH3SNa in acetone

SN2 (2° halide, strong nucleophile, polar aprotic solvent)

2° triflate (OSO2CF3) + CH3OH

SN1 (excellent LG, weak neutral Nu, polar protic solvent)

SN2 vs SN1 stereochemical outcome

SN2 = inversion. SN1 = racemization