Formation of Hydrates

hydrate

Summary

• Aldehydes and ketones react with water to give 1,1-geminal diols known as hydrates.
• In general, hydrates are not stable enough to be isolated as the equilibrium shifts back to starting materials.
• However, hydrates are the reactive species in the oxidation of aldehydes to acids.
• Understanding the mechanism is useful before looking at the very closely related reactions of alcohols.

• Formation of Acetals
• Hydrolysis of Esters

MECHANISM FOR THE ACID catalyzed FORMATION OF HYDRATES
Step 1: An acid/base reaction. Since there is only a weak nucleophile we need to activate the carbonyl by protonating on O.
Step 2: The nucleophilic O in the water attacks the electrophilic C in the C=O, breaking the p bond and giving the electrons to the positive O.
Step 3: An acid/base reaction. Deprotonation of the oxonium ion neutralizes the charge giving the hydrate.

Reactions of Alcohols to give Acetals

hemi-acetal                                  acetal

Reaction type:  Nucleophilic Addition then nucleophilic substitution

Summary

• Typical reagents : excess ROH, catalytic p-toluenesulfonic acid (often written as TsOH) in refluxing benzene.
• Aldehydes and ketones react with two moles of an alcohol to give 1,1-geminal diethers more commonly known as acetals.
• The term "acetal" used to be restricted to systems derived from aldehydes and the term "ketal" applied to those from ketones, but chemists now use acetal to describe both.
• Acetals are biologically important due to their role in the chemistry of carbohydrates.
• Acetals are important chemically due to their role as "protecting groups"
• The equilibrium is shifted towards the acetal by using an excess of the alcohol and/or removing water as it forms.
• It is also possible to use 1,2- or 1,3-diols to form cyclic acetals, two common examples are shown below:

• Acetals can be readily converted back to the aldehyde or ketone by heating with aqueous acid.
• The mechanism for this is the reverse of that shown below for acetal formation.

Related Reactions

• Formation of Hydrates
• Synthesis of Esters

MECHANISM FOR THE ACID catalyzed FORMATION OF ACETALS
Step 1: An acid/base reaction. Since there is only a weak nucleophile we need to activate the carbonyl by protonating on O.
Step 2: The nucleophilic O in the alcohol attacks the electrophilic C in the C=O, breaking the p bond and giving the electrons to the positive O.
Step 3: An acid/base reaction. Deprotonation of the alcoholic oxonium ion neutralizes the charge giving the hemi-acetal.  Now we need to substitute the -OH by -OEt.
Step 4: An acid/base reaction. In order for the -OH to leave we need to make it into a better leaving group by protonation.
Step 5: Using the electrons from the other O, the leaving group departure is facilitated.
Step 6: We now have what resembles a protonated ketone (compare with step 2).  The nucleophilic O of the alcohol attacks the electrophilic C and the electrons of the p bond move to neutralize the charge on the positive O.
Step 7: An acid/base reaction. Deprotonation of the alcoholic oxonium neutralizes the charge and produces the acetal product and regenerates the acid catalyst.

Protecting Groups

• Protecting groups are used in synthesis to temporarily mask the characteristic chemistry of a functional group because it interferes with another reaction.
• A good protecting group should be easy to put on, easy to remove and in high yielding reactions, and inert to the conditions of the reaction required.
• For example, consider the following scenario: How can you perform the following reaction ?

The overall transformation required is ester to primary alcohol.  This is a reduction of the ester, which requires LiAlH4, but that will reduce the ketone as well which we don't want. We can avoid this problem if we "change" the ketone to a different functional group first. Conceptually, this is like being able to put a cover (shown below) over the ketone while we do the reduction, then remove the cover.

In reality, the "molecular cover" is a protecting group. In this example, we protect the ketone as an acetal (which is an ether and doesn't react with LiAlH4)

Then we can reduce the ester to the primary alcohol.

Finally we can remove the protecting group:

Overall, this gives us the complete scheme: