21.3. Formation of hydrates, hemiacetals, acetals

 

Addition of water to aldehydes/ketones to form hydrates

Geminal diols, usually referred to as hydrates of aldehydes or ketones, have two hydroxy groups attached to the same carbon; the carbon has the same oxidation state as the corresponding C=O.  Like most carbonyl equivalents, hydrates are usually unstable compared to the C=O, which is why they can only rarely be isolated as stable compounds.  However, when electron withdrawing groups (such as -CF3, -CCl3 or another C=O) are attached to the C=O, the hydrate is stable enough to be made and isolated.  One such compound is chloral hydrate, formerly used as a sedative and as a knockout drug called a “Mickey Finn” in old gangster movies!

Water is a weak nucleophile, and therefore it will only add to a carbonyl (aldehyde or ketone) that has been activated by H+ to form its conjugate acid.  The mechanism is exactly as shown in section 21.1.  Using acetone as an example, the oxygen is first protonated to give the activated ketone; water adds via nucleophilic addition, then H+ is lost again via a second acid-base reaction.  (A second water molecule has been used here as the base to remove the H+.)

Mechanism for formation of acetone hydrate from acetone, by attachment of H+, nucleophilic addition of H2O then loss of H+.

Addition of alcohols to form hemiacetals and acetals

Like water, alcohols are weak nucleophiles, and so again they will only add to a protonated carbonyl.  The initial addition of one alcohol leads to a hemiacetal, analogous to a hydrate. The hemiacetal is not normally a stable end product; typically the process continues by losing a molecule of water then adding a second alcohol molecule to give finally an acetal.  The entire process is reversible, and requires removal of water (using Le Chatelier’s principle) to drive the reaction to completion and give the acetal product.  Both hemiacetals and acetals (as typical carbonyl equivalents) will easily revert to the carbonyl compound in the presence of added water, using the same acid catalysis. This is a good example of the principle of microscopic reversibility; the acid catalyst lowers the energy barrier for both the forward and backward reactions.  The reaction is shown using acetone as an example ketone.

Sometimes acetals made from ketones are referred to as ketals.  Note that only aldehydes and ketones react with alcohols in this way; esters and other carboxylic acid derivatives will not give isolable addition products even if water is removed.

In the laboratory, there are a couple of ways we can remove water.  One is to use a Dean-Stark trap, that allows water to separate out from a boiling mixture and be removed.  The other is to use molecular sieves – a form of activated clay that traps water inside its structure.

Detailed mechanism for acetal formation

As mentioned above, the formation of the hemiacetal is very similar to formation of a hydrate.  Starting from acetone 1, H+ is attached to form the conjugate acid 2, then ROH adds via nucleophilic addition to form 3, and finally H+ is lost to give hemiacetal 4.  This marks a useful mid-point in the mechanism.

To go from the hemiacetal to the acetal, we need first to remove the OH group.  This is done by attaching H+ to the oxygen of the OH, giving 5, which is very similar in structure to 3.  This can then lose water (by nucleophile elimination) to give an alkylated ketone 6, analogous to structure 2.  As we can see, to go from 4 to 5 to 6 we have gone through two steps that match the reverse reaction from 4 to 3 to 2.  At this point, the mechanism starts going “forward” again, with a nucleophilic addition to 6 to give 7, which then loses H+ via acid-base to give the final acetal 8.  These two steps from 6 to 7 to 8 exactly match the earlier sequence 2 to 3 to 4 which formed the hemiacetal.

Acetals as protecting groups

Although acetals are unstable in the presence of aqueous acid, they are completely stable to most bases and nucleophiles.  This makes them useful as protecting groups (see section 15.2.) for aldehydes and ketones for reactions involving strong nucleophiles such as RMgX or LiAlH4 which react with C=O but not with an acetal.  After reaction (elsewhere) with the strong nucleophile, the protecting group can easily be removed with aqueous acid (H3O+) to regenerate the original C=O.  In the example shown, a Grignard reagent is made to selectively attack an ester group in the presence of a protected C=O; the workup of the Grignard reaction also serves to regenerate the ketone.

A compound with both a ketone and an ester has the ketone protected as an acetal. EtMgBr then reacts selectively with only the ester, and the ketone is regenerated using H3O+.

Cyclic acetals and hemiacetals in nature and in synthesis

Although simple acetals and hemiacetals are unstable in the presence of aqueous acid, they are greatly stabilized when their formation gives a new ring.  Where you have an alcohol and a carbonyl in the same chain, these will form a cyclic acetal or hemiacetal.  This is often seen in nature in carbohydrates such as glucose.  In the diagram below, the open chain form of glucose is shown with the OH and a C=O highlighted; this makes up less than 0.02% of the total glucose even in aqueous solution, and it easily cyclizes to give the more stable cyclic hemiacetal. If another alcohol group (such as fructose) replaces the hemiacetal OH in glucose this makes a full acetal, such as sucrose.

Examples of a stable natural cyclic acetal (sucrose) and hemiacetal (glucose)

More stable acetals can also be made from aldehydes and ketones by using a diol such as ethane-1,2-diol (ethylene glycol, HOCH2CH2OH) and propane-1,3-diol (HOCH2CH2CH2OH).  Such acetals are often used as protecting groups in synthesis.

References

  1. Vollhardt, K. Peter C., and Neil E. Schore. Organic Chemistry: Structure and Function. New York: W.H. Freeman and Company, 2007
  2. Carey, Francis. Advanced Organic Chemistry. 5th ed. Springer, 2007.

Contributors

  • Martin A. Walker, SUNY Potsdam

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