• Unless the -OH group is converted into a better leaving group, then alcohols are poor substrates for substitution reactions.
• Protonation to convert the leaving group into H₂O has limited utility as not all substrates or nucleophiles can be utilized under acidic conditions without unwanted side reactions.
• An alternative is to convert the alcohol into a tosylate, which has a much better leaving group and will react with nucleophiles without the need for the acid.

• Preparation and Reaction of Tosylates
• Reaction of Alcohols with Hydrogen Halides (review)
• Reaction of Alcohols with SOCl₂, PCl₃, PBr₃ (review)

Reaction type: Nucleophilic Substitution (usually S_N2)

Summary:

• Alcohols can be converted into tosylates using tosyl chloride and a base to "mop-up" the HCl by-product.
• Tosylates are good substrates for substitution reactions.
• Used mostly for 1^o and 2^o ROH (S_N2 reaction).
• The -OH reacts first as a nucleophile, attacking the electrophilic center of tosylate, displacing a Cl.
• Tosylates have a much better leaving group : the conjugate base of tosic acid, pKa = -2.8
• The advantage of this method is that the substitutions reactions are not under the strongly acidic conditions.
• Tosylates will react with nucleophiles in much the same way as alkyl halides.
• Alternatives to tosylates are mesylates (use CH₃SO₂Cl) and triflates (use CF₃SO₂Cl)

	This is the reagent used to prepare the tosylate ester. It maybe referred to by any of the terms shown.
	The tosylate ester is shown. Note that the oxygen atom from the original alcohol is retained.
	In the reactions of tosylates, the displaced group is the resonance stabilized anion shown which is a good leaving group.

Reaction of Alcohols with Hydrogen Halides
(review of chapter 4)

Reaction type: Nucleophilic Substitution (S_N1 or S_N2)

Summary:

• When treated with HBr or HCl alcohols typically undergo a nucleophilic substitution reaction to generate an alkyl halide and water.
• Alcohol relative reactivity order : 3^o > 2^o > 1^o > methyl.
• Hydrogen halide reactivity order : HI > HBr > HCl > HF (paralleling acidity order).
• Reaction usually proceeds via an S_N1 mechanism which proceeds via a carbocation intermediate, that can also undergo rearrangement.
• Methanol and primary alcohols will proceed via an S_N2 mechanism since these have highly unfavorable carbocations.
• The reaction of alcohols with HCl in the presence of ZnCl₂ (catalyst) forms the basis of the Lucas test for alcohols.

SN1 MECHANISM FOR REACTION OF ALCOHOLS WITH HBr Step 1: An acid/base reaction. Protonation of the alcoholic oxygen to make a better leaving group. This step is very fast and reversible.  The lone pairs on the oxygen make it a Lewis base.       Step 2: Cleavage of the C-O bond allows the loss of the good leaving group, a neutral water molecule, to give a carbocation intermediate. This is the rate determining step (bond breaking is endothermic)         Step 3: Attack of the nucleophilic bromide ion on the electrophilic carbcation creates the alkyl bromide.

 

Reaction of Alcohols with other Halogenating agents (SOCl₂, PX₃)
(review of chapter 4)

Reaction type: Nucleophilic Substitution (S_N1 or S_N2)

Summary:

• Alcohols can also be converted to alkyl chlorides using thionyl chloride, SOCl₂, or phosphorous trichloride, PCl₃.
• Alkyl bromides can be prepared in a similar reaction using PBr₃.
• Used mostly for 1^o and 2^o ROH (S_N2 reaction)
• In each case a base is used to "mop-up" the acidic by-product.
• Common bases are triethylamine, Et₃N, or pyridine, C₆H₅N.
• In each case the -OH reacts first as a nucleophile, attacking the electrophilic center of the halogenating agent.
• A displaced halide ion then completes the substitution displacing the leaving.
• Note that it is not -OH that leaves, but a much better leaving group.
• The advantage of these reagents is in that the reaction is not under the strongly acidic conditions like using HCl or HBr.