Hydroxy and Keto Acids

Hydroxy Acids and their Structure

There is a very important class of organic compounds that contain alcohol and carboxyl groups at
the same time. These are hydroxy acids. The placement of the functional groups can vary. Thus, one has ɑ-,
β-, γ-, δ-, ε-hydroxy acid and so on.

Figure 1. ɑ-, β- and γ-hydroxy acids

Secondary alcohol group:

Most often, the alcohol group in question is a secondary alcohol group. The main fragment of an ɑ-
hydroxy acid contains hydroxy- and carboxyl groups attached to the same α-carbon atom that may also
have one or more side chains as depicted on the figure below:

Figure 2. An ɑ-hydroxy acid

If the ɑ-Carbon contains two different substituents (the other two, being hydroxy- and carboxyl
groups, are always different from each other), than it presents a stereogenic center. Therefore, if an ɑ-
hydroxy acid is a secondary alcohol, it always contains a stereogenic center in the ɑ-position. As for β-, γ-,
δ-, ε-hydroxy acids, we have to ascertain the presence of stereogenic centers by the common rules.
 Stereogenic carbon is in the sp3
hybridization state and contains four
different substituents.

Let us review a list of most important hydroxy acids:

Table 1. Most important hydroxy acids

Structure Common Name IUPAC Name

Glycolic acid Hydroxyethanoic acid

Lactic acid 2-hydroxy-propanoic acid

Malic acid 2-hydroxy-butandioic acid

Tartaric acid 2,3-dihydroxy-butandioic acid

 Citric acid 3-carboxy-3-hydroxy-pentandioic acid

Isocitric acid 3-carboxy-2-hydroxy-pentandioic acid

The easiest way to remember the structures is first to remember the

IUPAC name and then to draw the structure on the basis of that IUPAC
name. As you see, the IUPAC names are really easy.

As we see, some of α-hydroxy acids have a side chain that also contains another carboxyl group.
Such hydroxy acids are di- or triprotic acids. For example, malic acid and tartaric acid are diprotic acids, and
citric acid and isocitric acid are triprotic acids. Di- and triprotic hydroxy acids can be ɑ-, β-, γ-, acids at the
same time. Malic acid and citric acid are ɑ- and β-hydroxy acids, whereas isocitric acid is ɑ-, β- and γ-
hydroxy acid.

Glycolic acid and citric acid do not contain stereogenic centers. They are symmetric compounds.
Tartaric acid can contain two stereogenic centers but two of its four possible configurations are symmetric
and present the identical meso-compound, therefore tartaric acid has three configurations: (-)-tartaric acid,
(+)-tartaric acid and meso-tartaric acid. Isocitric acid has two different stereogenic centers but none of its
four configurations is symmetric; that is why isocitric acid may present four distinct configurations.
 Meso-compound is a symmetric compound containing two
or more stereogenic centers. As the optical activity is a function
of symmetry (rather, its absence), meso-compounds are optically
inactive.

Figure 3. This is how a hydroxy acid can be an ɑ- and β-hydroxy acid at the same time.

Chemical Properties of Hydroxy Acids

It is obvious that both the alcohol and carboxy groups retain their properties and, therefore,
hydroxy acids can produce the whole set of compounds characteristic to alcohols and carboxylic acids. It
should be kept in mind, however, that both groups offer the electron-withdrawing effect and can influence
the characteristic reactions. Protection of hydroxy groups (by converting them into ether) improves the
yield of reactions of carboxyl group and vice versa. It is noteworthy that α-hydroxy acids are significantly
stronger than corresponding unsubstituted carboxylic acids.

Electron-withdrawing groups improve the acidity of the carboxyl group. The

shorter the distance between these groups, the more significant the effect
is.
 Examination of the products of heating hydroxy acids allows for identification of the position of the
hydroxy group with respect to the carboxyl group.

Heating of α-hydroxy acids produces lactides that are cyclic diesters:

These lactides hydrolyze back to the original ɑ-hydroxy acids whenever conditions are acidic or alkaline.

If the ɑ-Carbon of a β-hydroxy acid contains a hydrogen atom, then its mobility is so high that it can
be eliminated relatively easily. That is why heating of β-hydroxy acids produces so called ɑ, β-unsaturated
carboxylic acids:

H- OH

Heating of γ- and δ-hydroxy acids yields cyclic monoesters, γ- and δ-lactones, correspondingly:

They also hydrolyze back to initial hydroxy acids in acidic or alkaline media. It is curious to observe
that there can exist ɑ- and β-lactones but, being three and four member rings, they are utterly unstable.

Dehydration of ɑ-hydroxy acids is also possible and they, just like β-hydroxy acids, produce ɑ, β-
unsaturated carboxylic acids. What is particularly important is that the rehydration of the latter produces a
β-hydroxy acid. This is how an ɑ-hydroxy acid can be reformed into a β-hydroxy acid. Exactly this process is
responsible for conversion of citric acid into isocitric acid in the Krebs cycle. The intermediate ɑ, β-
unsaturated carboxylic acid is aconitic acid. The conversion is guided by a complex organometallic
coenzyme.

Another important reaction of ɑ-hydroxy acids is oxidative decarboxylation, which is achieved by

heating of the aqueous solution of the ɑ-hydroxy acid in the presence of strong mineral acids such as HCl:

 +

Notice that decarboxylation does not yield an alcohol. What is yielded here is an oxidized analog of
primary and secondary alcohols - a carbonyl compound. Hence the name of the process. Whichever is the
ɑ-hydroxy acid that undergoes oxidative decarboxylation, the by-product is always the same: formic acid.

It is noteworthy that, if there is another carboxyl group in the side chain

(I.e., the hydroxy acid in question is a diprotic or triprotic), then the
side chain carboxyl is not eliminated.

If the ɑ-Carbon of an ɑ-hydroxy acid is chiral, then it can undergo Walden inversion:

The first step of the process presents an SN2 halogenation of malic acid and implies inversion of
configuration of the stereogenic center. The second step is hydrolysis of a halide via S N1, that means that
one has a partial retaining of configuration. Overall, Walden inversion allows for partial conversion of D-
hydroxy acids into L-hydroxy acids.

The most important representatives of hydroxy acids participate in the Krebs cycle as well as in the
glycolytic pathway.
 There are also phenolic compounds that contain carboxy groups. The most important
representatives are salicylic acid, aspirin and gallic acid.

Table 2. Some important phenolic acids

Structure Common Name IUPAC Name

Salicylic acid 2-hydroxy-benzoic acid

Aspirin 2-acetoxy-benzoic acid

Gallic acid 3,4,5-tryhydroxy-bezoic acid

Keto Acids

Keto acids are oxidized analogs of hydroxy acids which means that the alcohol function of hydroxy
acids is oxidized to carbonyl function. The opposite is also true: hydroxy acids should be considered
reduced analogs of hydroxy acids. For example, pyruvic acid (see Table 3) is reduced to lactic acid during
the glycolytic pathway. Whenever the reverse process (I.e., oxidation of lactic acid to pyruvic acid) is
absent, lactic acid accumulates and results in a characteristic muscular pain of exhaustion. After resting,
the oxygen content is regenerated, and lactic acid is oxidized back to the pyruvic acid.
The position of the carbonyl group with respect to the carboxyl group can vary, just like it happens
in hydroxy acids. Therefore, we also have ɑ-, β-, γ-, δ-, ε-hydroxy acid and so on. Of the aforementioned,
most important are ɑ- and β-keto acids.

Figure 4. ɑ-, β- and γ-keto acids

Usually, keto acids are ketones, but some important representatives can be aldehydes, such as
glyoxalic acid and formylacetic acid.

Figure 2. An ɑ-keto acid

Let us consider some important representatives.
Table 3. Most important hydrox acids

Structure Common Name IUPAC Name

Glyoxalic acid Oxaldehyc acid or oxo-ethanoic acid

Pyruvic acid 2-oxo-propanoic acid

Formylacetic acid 3-oxo-propanoic acid

Oxaloacetic acid 2-oxo-butanedioic acid

α-Ketoglutaric acid 2-oxopentanedioic

α-Ketobutiric acid 2-oxo-butanoic acid

 α-Ketovaleric acid 2-oxo-pentanoic acid

As both the carbonyl and the carboxyl groups are powerful electron-withdrawing groups,
they have positive effect on the reactivity of each other especially when they are placed at the α-position.
Gem-diols (carbonyl hydrates) of α-keto acids are much more stable than those of unsubstituted ketones:

Chemical Properties of α-Keto Acids

The most important properties of α-keto acids are decarboxylation and decarbonylation reactions.
In vitro, the reactions are carried out with the help of sulfuric acid. Heating is required.

heating, H2SO4, dil.

Figure 6. Decarboxylation of pyruvic acid. The same reaction carries out similarly for other α-keto
acids.
 heating, H2SO4, conc.
CO

Figure 7. Decarbonylation of pyruvic acid. The same reaction carries out similarly for other α-keto
acids.

It is easy to confuse diluted sulfuric acid for concentrated sulfuric acid. Notice that the
decarbonylation results in an oxidized form. Indeed, simple decarboxylation produced aldehyde that
oxidizes easily to the carboxylic acid that is the product of decarbonylation. Recall that concentrated
sulfuric acid possesses significant oxidation power. That is why decarbonylation of α-keto acids is referred
to as oxidative decarboxylation.

It is noteworthy that, if there is another carboxyl group in

the side chain (I.e., the hydroxy acid in question is a diprotic
or triprotic), then the side chain carboxyl is not eliminated.

In vivo analogs of the aforementioned reactions are of paramount importance. Oxidative

decarboxylation of pyruvic acid to acetyl-CoA is mediated with wo coenzymes, thiamine diphosphate (TPP),
that is produced with vitamin B1, and lipoic acid. This process triggers the Krebs cycle. On a later stage of
this cycle, one encounters decarboxylation of α-ketoglutaric acid to succinyl CoA. It is essentially the same
process.

Coenzyme A is an important substance and presents a molecule with a

fairly complicated structure. It contains residues of ADP, pantothenic acid
and cysteamine. The crucial aspect is that coenzyme A is a thiol and
contains the -SH group. Any AcylCoA therefore is a thioester.

However, α-ketoglutaric acid is prepared by decarboxylation of oxalosuccinic acid that is produced

by oxidation of isocitric acid. Decarboxylation of oxalosuccinic acid is a property of β-keto acids and is
based on a completely different mechanism involving keto-enol tautomerism.

Formation of enol forms of β-keto acids is easier as the α-Hydrogen is placed between two
powerful electron-withdrawing groups (the carboxyl group and the carbonyl group in the β-position). The
resultant enol is subject to producing an intramolecular hydrogen bond that is responsible for an increased
stability of the enol form.
 The enol form of the β-keto acid allows for elimination of the main carboxyl group, hence an easy
decarboxylation of β-keto acids.

20% 80%

hydrogen bond

Figure 8. Keto and enol forms of oxaloacetic acid.

Here is how the decarboxylation of β-keto acids proceeds eventually:

Finally, we have to keep in mind that, as mentioned above, keto acids offer the complete set of
reactions of aldehydes or ketones and carboxylic acids.