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3.12: Prochirality

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  • Prochiral carbons

    When a tetrahedral carbon can be converted to a chiral center by changing only one of the attached groups, it is referred to as a ‘prochiral' carbon. The two hydrogens on the prochiral carbon can be described as 'prochiral hydrogens'.

    Prochiral carbon attached to two R groups and two hydrogens (blue dashed and red wedged). Text: prochiral hydrogens. Change the red H to D to form a chiral carbon.

    Note that if, in a 'thought experiment', we were to change either one of the prochiral hydrogens on a prochiral carbon center to a deuterium (the 2H isotope of hydrogen), the carbon would now have four different substituents and thus would be a chiral center.

    Prochirality is an important concept in biological chemistry, because enzymes can distinguish between the two ‘identical’ groups bound to a prochiral carbon center due to the fact that they occupy different regions in three-dimensional space. Consider the isomerization reaction below, which is part of the biosynthesis of isoprenoid compounds. We do not need to understand the reaction itself (it will be covered in chapter 14); all we need to recognize at this point is that the isomerase enzyme is able to distinguish between the prochiral 'red' and the 'blue' hydrogens on the isopentenyl diphosphate (IPP) substrate. In the course of the left to right reaction, IPP specifically loses the 'red' hydrogen and keeps the 'blue' one.

    Isopentenyl diphosphate in equilibrium with dimethylallyl diphosphate. One hydrogen is removed and the alkene moves from carbons 1 and 2 to carbons 2 and 3.

    Prochiral hydrogens can be unambiguously designated using a variation on the R/S system for labeling chiral centers. For the sake of clarity, we'll look at a very simple molecule, ethanol, to explain this system. To name the 'red' and 'blue' prochiral hydrogens on ethanol, we need to engage in a thought experiment. If we, in our imagination, were to arbitrarily change red H to a deuterium, the molecule would now be chiral and the chiral carbon would have the R configuration (D has a higher priority than H).

    Carbon attached to methyl, O H and 2 hydrogens (blue on dash and red on wedge). Red H is changed to D and the stereocenter is now R. If the dashed H (blue) had been changed to D, the stereocenter would be S.

    For this reason, we can refer to the red H as the pro-R hydrogen of ethanol, and label it HR. Conversely, if we change the blue H to D and leave red H as a hydrogen, the configuration of the molecule would be S, so we can refer to blue H as the pro-S hydrogen of ethanol, and label it HS.

    Looking back at our isoprenoid biosynthesis example, we see that it is specifically the pro-R hydrogen that the isopentenyl diphosphate substrate loses in the reaction.

    Isopentenyl diphosphate in equilibrium with dimethylallyl diphosphate. One hydrogen is removed and the alkene moves from carbons 1 and 2 to carbons 2 and 3.

    Prochiral hydrogens can be designated either enantiotopic or diastereotopic. If either HR or HS on ethanol were replaced by a deuterium, the two resulting isomers would be enantiomers (because there are no other stereocenters anywhere on the molecule).

    Left: Carbon attached to methyl, hydroxyl group and enatiotopic hydrogens (two hydrogens; one on wedge and one on dash). Right: Both variations after one H has been replaced by a D group (one with D wedged and one with D dashed). Text states they are enantiomers of each other.

    Thus, these two hydrogens are referred to as enantiotopic.

    In (R)-glyceraldehyde-3-phosphate ((R)-GAP), however, we see something different:

    Left: (R)-GAP molecule with diastereotopic hydrogens (H R on dashes and HS on wedge). Right: (R)-GAP molecules but with one H replaced by a D. Replacing H S results in an S R molecule and replacing H R results in a R R molecule. Text shows they are diastereomers of each other.

    R)-GAP already has one chiral center. If either of the prochiral hydrogens HR or HS is replaced by a deuterium, a second chiral center is created, and the two resulting molecules will be diastereomers (one is S,R, one is R,R). Thus, in this molecule, HR and HS are referred to as diastereotopic hydrogens.

    Finally, hydrogens that can be designated neither enantiotopic nor diastereotopic are called homotopic. If a homotopic hydrogen is replaced by deuterium, a chiral center is not created. The three hydrogen atoms on the methyl (CH3) group of ethanol (and on any methyl group) are homotopic.

    Molecule with homotopic hydrogens. Three hydrogens attached to carbon on methyl group (in red).

    An enzyme cannot distinguish among homotopic hydrogens.

    Exercise 3.29

    Identify in the molecules below all pairs/groups of hydrogens that are homotopic, enantiotopic, or diastereotopic. When appropriate, label prochiral hydrogens as HR or HS.

    a: dihydrorotate; a nucleotide biosynthesis intermediate. b: phosphoenolpyruvate (a glycolysis intermediate). c: succinate (a citric acid cycle intermediate). d: pyruvate (endpoint of glycolysis).

    Solutions to exercises

    Groups other than hydrogens can be considered prochiral. The alcohol below has two prochiral methyl groups - the red one is pro-R, the blue is pro-S. How do we make these designations? Simple - just arbitrarily assign the red methyl a higher priority than the blue, and the compound now has the R configuration - therefore red methyl is pro-R.

    Carbon attached to a hydroxyl group, an ethyl group and two methyl groups (one on dashes on and one on a wedge). Wedged methyl labeled methyl A (pro-r). Dashed methyl labeled methyl B (pro-S).

    Citrate is another example. The central carbon is a prochiral center with two 'arms' that are identical except that one can be designated pro-R and the other pro-S.

    Citrate molecule. Two identical "arms" (C H 2 C O 2 minus); one red and one blue. Red labeled pro-R arm and blue labeled pro-S arm.

    In an isomerization reaction of the citric acid (Krebs) cycle, a hydroxide is shifted specifically to the pro-R arm of citrate to form isocitrate: again, the enzyme catalyzing the reaction distinguishes between the two prochiral arms of the substrate (we will study this reaction in chapter 13).

    Citrate molecule with hydroxide on carbon 3 (carbon that connects pro-R arm and pro-S arm). Equal sign towards citrate molecule drawn from a different perspective. Arrow from citrate to isocitrate. Text: hydroxide moved specifically to the pro-R arm.

    Exercise 3.30

    Assign pro-R and pro-S designations to all prochiral groups in the amino acid leucine. (Hint: there are two pairs of prochiral groups!). Are these prochiral groups diastereotopic or enantiotopic?

    Molecule of leucine.

    Solutions to exercises

    Although an alkene carbon bonded to two identical groups is not considered a prochiral center, these two groups can be diastereotopic. Ha and Hb on the alkene below, for example, are diastereotopic: if we change one, and then the other, of these hydrogens to deuterium, the resulting compounds are E and Z diastereomers.

    Alkene with two hydrogens on left carbon (H A pointing up and H B pointing down). Two structures of the same alkene; right molecule has H A changed to D (Z-alkene) and left molecule has H B changed to D (E-alkene). Diastereomers of each other.

    Prochiral carbonyl and imine groups

    Trigonal planar, sp2-hybridized carbons are not, as we well know, chiral centers– but they can be prochiral centers if they are bonded to three different substitutuents. We (and the enzymes that catalyze reactions for which they are substrates) can distinguish between the two planar ‘faces’ of a prochiral sp2 - hybridized group. These faces are designated by the terms re and si. To determine which is the re and which is the si face of a planar organic group, we simply use the same priority rankings that we are familiar with from the R/S system, and trace a circle: re is clockwise and si is counterclockwise.

    Left: carbon with three atoms of different priorities. First priority pointing up, second priority pointing right and third priority pointing left. Text: looking at the re face. Right: same molecule with third priority atom pointing right. Counterclockwise rotation. Text: looking at the si face.

    Below, for example, we are looking down on the re face of the ketone group in pyruvate:

    Pyruvate molecule. Carbonyl priority #1 circled in red. Carboxylate priority #2 circled in blue. Methyl group #3 circled in green.

    If we flipped the molecule over, we would be looking at the si face of the ketone group. Note that the carboxylate group does not have re and si faces, because two of the three substituents on that carbon are identical (when the two resonance forms of carboxylate are taken into account).

    As we will see in chapter 10, enzymes which catalyze reactions at carbonyl carbons act specifically from one side or the other.

    Text: we are looking at the si face of the ketone.

    We need not worry about understanding the details of the reaction pictured above at this point, other than to notice the stereochemistry involved. The pro-R hydrogen (along with the two electrons in the C-H bond) is transferred to the si face of the ketone (in green), forming, in this particular example, an alcohol with the R configuration. If the transfer had taken place at the re face of the ketone, the result would have been an alcohol with the S configuration.

    Exercise 3.31

    For each of the carbonyl groups in uracil, state whether we are looking at the re or the si face in the structural drawing below.

    Molecule of uracil.

    Solutions to exercises

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