Alcohols to Good Leaving Groups
Hydroxyl, OH, is a poor leaving group
The hydroxyl group, OH is a poor leaving group. This makes alcohols poor electrophiles. Nucleophiles will not attack the R group of an alcohol because there is not a good leaving group.
But, the good news is there are several ways to turn the poor hydroxyl leaving group into a good leaving group.
Turn OH into H2O
In the presence of a strong acid, the hydroxyl group can be protonated. Once protonated, it turns into a water leaving group. Water is a wonderful leaving group because it is a stable molecule. In the example below, an alcohol reacts with HBr, a good acid. The very negative lone pair of electrons of the hydroxyl group attack the proton of HBr. This makes the positively charged water leaving group. This leaving group can leave, making a carbocation. Br- attacks the carbocation giving an alkyl bromide.
2. Which of the following alcohols would react the fastest with HBr to make an alkyl bromide? Hint: remember what type of intermediate is made in the reaction.
Dehydration
To form an ether
The hydroxyl group of alcohols is a poor leaving group. But, in the presence of a strong, dehydrating, acid like sulfuric acid, H2SO4, or phosphoric acid (H3PO4) it can be turned into a good leaving group (H2O). The bimolecular (two-molecule) dehydration (loss of H2O) that occurs between two alcohols produces an ether.
This is only an effective synthesis for symmetrical ethers; two identical alcohols should be used. If two different alcohols are used, it leads to a mixture of products. Because of this difficulty, this is a good way to make ethers industrially, but this method is not usually used in the lab.
The mechanism for this ether-forming dehydration involved protonating a hydroxyl group of an alcohol to make the great, stable, H2O leaving group. The other alcohol attacks via an SN2, backside-attack mechanism. After cleaning it up, an ether is formed. Below, see the mechanism for the dehydration of two molecules of ethanol to form diethyl ether. This dehydration to form an ether tends to happen between 130-140°C. Above this temperature, a different, competing reaction tends to happen. This sensitivity to temperature is one of the reasons this reaction is not usually performed in the laboratory. There are better ways to make ethers.
Bimolecular dehydration of ethanol to form diethyl ether
To form an alkene
The competing dehydration of alcohols is the unimolecular dehydration to form an alkene. This dehydration tends to occur at temperatures over 140°C. It occurs via an E1 reaction mechanism. The acid used is usually a good dehydrating acid like sulfuric acid, H2SO4, phosphoric acid, H3PO4, or p-toluenesulfonic acid (tosic acid, p-TsOH).
Because a carbocation is formed in this E1 reaction, rearrangements are common. Also, because a carbocation is formed in this reaction, tertiary alcohols react faster than secondary alcohols because more stable carbocations are formed. Primary and methyl alcohols react slowly because an undesirable primary or methyl carbocation would be formed.
When an alkene is formed from dehydration, the Saytzeff product (more substituted double bond) is the one that is usually formed.
3. Draw the major alkene or ether products of the following dehydration reactions.
a)
b)
c)
d)
e)
Turning OH into a halide
We have seen previously how an OH group can be turned into a halide. Halides, of course, are good leaving groups.
Tertiary alcohols react with HCl, HBr, or HI to make the appropriate alkyl halide. Secondary alcohols work slower this way. Primary and methyl alcohols do not work well with this method.
An easy way to generate HBr is to use NaBr and H2SO4.
Sometimes zinc chloride, ZnCl2, is used with HCl to turn a secondary or tertiary alcohol into a chloride. This combination of ZnCl2 and HCl is called the Lucas reagent.
In fact, the Lucas reagent can be a chemical test to help determine if an alcohol is a primary, secondary, or tertiary alcohol. This is called a Lucas test. In this test, an alcohol reacts with the Lucas reagent. If the reaction proceeds rapidly, less than 1 minute, it indicates a tertiary alcohol was used. If the reaction takes 1-5 minutes, it indicates a secondary alcohol was used. If the reaction is slower than that, it indicates an unreactive primary alcohol was used.
One drawback to using a strong acid like HCl or HBr to make an alkyl halide is a carbocation intermediate is formed in the process of the reaction. This can sometimes lead to undesired rearrangement products.
If we try to turn a primary or secondary alcohol into a halide, we need to use different reagents. We use thionyl chloride (SOCl2) to make chlorides, phosphorus tribromide (PBr3) to make bromides, and a combination of phosphorus and iodine (P/I2) to make iodides. When SOCl2 or PBr3 are used, rearrangements are uncommon because a carbocation intermediate is not formed.
Table. Best reagents to transform alcohols to halides
Of course, there are many other ways to turn hydroxyl groups into halides. The above are a first approximation on what to try, but if they do not work for you in a real-life lab situation, do not fret. There are plenty more ways to do this.
4. Draw the product of the following reactions.
a)
b)
c)
d)
e)
f)
g)
h)
i)
Turning OH into a sulfonate
Sulfonates are also very good leaving groups. Two common sulfonate leaving groups are toluenesulfonate and methanesulfonate. First, we’ll take a closer look at what these sulfonates are and why they are good leaving groups, then we will look at how they are made from alcohols.
Sulfonate names
Methyl benzene is called toluene.
A toluene sulfonate often called a tosylate is a toluene and a sulfonate together. A toluene sulfonate group is often called a tosyl group. When the tosylate is on an alkyl group, it is calls a tosylate ester (ROTs).
Tosylate ester
A methanesulfonate is often called a mesylate.
Mesylate ester
Tosylates and mesylates are great leaving groups. When they leave the alkyl group, they have a negative charge on the oxygen atom. This negative charge can be spread out over several atoms through resonance. In fact, these resonance forms make tosylates and mesylates even better leaving groups than halides like Cl- or Br-.
Tosylate resonance forms
Synthesis of tosylate esters
The most efficient way to synthesize a tosylate ester is to react an alcohol with toluenesulfonyl chloride, tosyl chloride (TsCl) and a base like pyridine.
The mechanism for this reaction is as follows:
Mechanism for the tosylation of an alcohol
5. What reagent should be used to perform the following reactions?
a)
b)
c)
d)
e)
f)
g)
Why turn an OH into a good leaving group?
If a hydroxyl group is turned into a good leaving group, our new alkyl halide or tosylate ester can be a good electrophile. A nucleophile can attack it with the new leaving group leaving. This opened up the possibility for several types of reaction from SN2 to E2 type reactions.
SN2
Ethers are often synthesized from alcohols. One alcohol is turned into an alkyl halide or a tosylate ester. With this good leaving group, it can be attacked by an alkoxide made from an alcohol and sodium. This SN2 reaction produces an ether. This is called the Williamson Ether Synthesis.
Williamson Ether Synthesis from alcohols
6. Synthesize the following compound, isopropyl methyl ether, using a Williamson Ether Synthesis starting from methanol and isopropanol. Hint: transform one alcohol into a halide and the other into an alkoxide.
E2
Also, alkyl halides and tosylate esters with their good leaving groups can do an elimination. For example, dehydrohalogenation with a good base makes an alkene via the E2 mechanism.
Dehydrohalogenation E2 reaction
7. Show the reaction of propanol with an appropriate reagent to turn it into a halide. Then add an appropriate base to make propene.
Answers
2. D
3. Draw the major alkene or ether products of the following dehydration reactions.
a)
b)
c)
d)
e)
4. Draw the product of the following reactions.
a)
b)
c)
d)
e)
f)
g)
h)
i)
5. What reagent should be used to perform the following reactions?
a)
b)
c)
d)
e)
f)
g)
6.
7.
