Fructose_ Molecular Modeling with CAChe

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					                                             Fructose: Molecular Modeling with CAChe
                                                            Binita Chandra
                                            Department of Chemistry, University of Pittsburgh
                                                              July 2006

Fructose is a simple sugar (monosaccharide) found in many foods and is one of the three most
important blood sugars along with glucose and galactose. It is a levorotatory sugar with the same
empirical formula as glucose (C6H12O6) but with a different structure. Glucose is a six carbon
aldehyde whereas fructose is a ketone.
                H                                                                                  H                    1
    H                       O       OH                                                     H
                                                                                                   6            O       CH2OH
                H                       2                                                          H
                H           OH                                                             5       H            OH          2
                4           3                                                                          4        3
   OH                               CH2OH                                                  OH                           OH
                OH          H                                                                      OH           H
                                                                    OH O
            -pyranose                                          5       3           OH             -pyranose
                                                       HO   6       4       2
            6                                                   OH OH
                                                                                                   6                    1
HOH2C                             OH                                                     HOH2C                        CH2OH
                H       O       OH                                                                     H            OH
                                                            open chain form                                 O
        5                               2                                                      5                            2
                    4           3                                                                      4            3
        H                           CH2OH                                                      H                        OH
                OH              H   1
                                                                                                       OH           H

            -furanose                                                                                 -furanose

Most monosaccharides exist as an equilibrium mixture of their cyclic and open forms in solution.
Fructose can exist in two different cyclic forms. If the C-5 hydroxyl group of fructose reacts with
the C-2 keto group, a five-membered ring is formed, whereas if the C-6 hydroxyl reacts, a six-
membered ring is formed. The six membered ring and the five membered ring are referred to as
the pyranose and furanose rings respectively. The nature of the substituent groups on the ring and
the configuration about the anomeric carbon (C-2 for fructose) will determine whether a given
monosaccharide prefers the furanose or pyranose structure. In an aqueous solution of fructose at
25 ˚C, the composition is 73% β-pyranose, 20% β-furanose, 5% α-furanose and 2% α-pyranose;
the acyclic keto form is negligible However in polysaccharides, fructose exists exclusively in the
furanose form1.
On Drawing Sugar molecules: The conventional way to draw carbohydrates is to keep the
anomeric carbon (the carbon attached to two oxygens, one of which is the ring oxygen) on the
right and the ring oxygen at the back. In the β-form, the anomeric OH group is on top of the ring
and in the α-form it is below the ring.

Part I
1. Six membered rings usually exist in chair forms. Draw the two possible chair forms of β-
pyranose below. Be careful in putting in all the axial and equatorial substituents.

                         C-2 OH equatorial                 C-2 OH axial

These are the two conformational isomers of β-fructopyranose. Conformational isomers can
interconvert between each other simply by rotation of bonds. No bonds need to broken. In
contrast, in order to convert β-pyranose to α-pyranose or vice versa, the bonds at the C-2 carbon
of the ring have to be broken and rearranged. These two forms are therefore not conformational
isomers. They are known as configurational isomers. Configurational isomers have the same
connectivities but may differ in configuration at one or more stereocenters.

2. Compare the two chair forms for the β-pyranose (your answers to Qn 1). By simply
looking at the sterics in the two structures which one would you predict to be the more
stable. Why?

3. Use CAChe to predict which form is the more stable by calculating their heats of

        ΔHf (C-2 OH equatorial) =                ΔHf (C-2 OH axial) =

Procedure for drawing and calculating ΔHf: First draw the β-pyranose chair of fructose which
has the C-2 hydroxyl group equatorial. Open the CAChe workspace program from the Start
menu. Click on the drawing pencil tool (5th from top on the left). Choose C/sp3 in the drop
down windows in the above left corner of the workspace window and click on the window. A
black ball should appear. Click in the center of this black ball, drag and release to join it to
another carbon. Draw a six membered ring by repeating this process. With the Select tool on the
left (first from top), click on one of the carbon atoms of the ring and select oxygen/sp3 on the top
drop down windows. Then click on the molecule using the Select Molecule tool on the left side
(second from top) and under the Beautify drop down menu on the top of the screen, click
Comprehensive. The chair form will appear with all the hydrogens. Press Ctrl F to centre the
structure on the window. Use the Rotate tool on the left (third from below) to reposition the
molecule to get a side-on view of the chair and then replace the axial and equatorial hydrogens
with the appropriate atoms to complete the structure. Make sure you select sp3 hybridization for
Oxygen. After the structure is drawn, click on the structure using the Select Molecule tool and
click Beautify/Comprehensive. Under the File drop down, select Save as, navigate to the My

Documents folder, save as BPeqtl.csf. Similarly draw the other chair which has the C-2 hydroxyl
group at the axial position and save as BPaxial.csf.

Now click on “Experiment/New” in the drop down menu on top of the workspace screen. In the
new window which appears, choose “chemical sample” under Property of, “optimized
geometry” under Property, “PM5 geometry in water” under Using. Click “Start”. Calculation
will begin. When it is finished, the molecule’s ΔHf value will be displayed at the end of the
calculation. Record this value in the space provided above. Repeat the same procedure to get the
ΔHf for the other chair conformer of β-pyranose.

4. Which is the more stable conformation according to CAChe? Does this match your

CAChe has predicted that this is the chair form in which the β-pyranose of fructose is most likely
to predominate. Is this true in real life? Yes, it is!! 1H NMR studies on aqueous solutions of
fructose have revealed that this is the only chair form of β-pyranose that can be detected at room
temperature. This means that the two chairs are so different in energies that at room temperature,
the energy barrier for going from the lower energy to the higher energy conformation, can not be
reached. Hence the equilibrium lies solely on the side of the low energy conformer.

5. The α-pyranose form of fructose also has two possible chair conformations. Draw both
the chairs below. Use CAChe to compute their ΔHf values as directed earlier. (Save the two
files by the names APeqtl.csf and APaxial.csf after drawing)

                           C-2 OH equatorial                   C-2 OH axial
                           ΔHf =                               ΔHf =

Notice, that the difference in the magnitude of ΔHf values in this case is much less than in the
case of the two β-pyranose chairs (your answers to Qn. 3).

 6. By simply looking at the structures which chair form would you predict to be the more
stable? Why?

There is evidence in the literature that the ring inversion equilibrium is important for α-
pyranose i.e. both forms are present in solution at room temperature. This would mean that
the two conformations are close in energies and so the C-2 OH axial form must be more stable
than what one would expect, based solely on sterics.

The phenomenon that stabilizes the “C-2 OH axial” conformation is called the Anomeric Effect,
 which states that electronegative substituents at the anomeric center of pyranoses prefer to adopt
an axial configuration. How is the anomeric effect explained? It can be explained by overlap of
the one of the lone pairs on oxygen with the antibonding *-orbital of the C-X bond (where X is
an electronegative element). Orbital overlaps cause lowering of energy and hence, have a
stabilizing effect. The overlap is efficient only when one of the electron lone pairs on the oxygen
is antiperiplanar with the C-X bond .This alignment can be achieved only when C-X bond is
axial (not equatorial).Therefore the axial form will be stabilized by the anomeric effect.

                                                                  In case of the β-pyranose, the
                                                                  anomeric and the steric effects act
                                                                  together in favour of the C-2 OH
                                                  X               axial chair conformer. The
                                                                  combined stabilizing effect makes
                                                                  this chair much more stable than
the other. On the other hand, for the α-pyranose, the two effects oppose one another, i.e. one
chair is favored sterically while the other chair is favored by the anomeric effect. Thus the
energy difference between them is not very great.

Now let us compare the relative stabilities of α-pyranose vs. β-pyranose.

6. NMR data suggest that the β-pyranose predominates in solution. Would you have
predicted the same? Why?

7. Draw the structures of α-furanose and β-furanose in CAChe (save them as AF.csf and
BF.csf respectively). Compute their heats of formation as before and record the values
below. Do your results agree with the known relative compositions?

ΔHf (α-furanose) =                                 ΔHf (β -furanose) =

Part II:
Disaccharides consist of two sugars joined by an O-glycosidic bond. Sucrose, common table
sugar, is a disaccharide made of glucose and fructose. Here, unlike in solution, fructose exists
100% in its furanose form. The anomeric configurations are α for the pyranose form of glucose
and β for the furanose form of fructose.

                     -glucose                                                                                                        -fructose
                                                HO       6                                               1
                                                     5               O
                                                H                            H                               H           O       OH
                                                     H                           1                   2                                   5
                                                     OH              H                                       3                   4
                                                         3           2
                                                OH                                       O                                           CH2OH
                                                                                                             OH                  H   6
                                                     H               OH


Sucrose is made up of the α-form of D-glucose and the β-form of D-fructose. In the diagram
above, note that the α-D-glucose is in the conventional orientation. The β-D-fructose, however, is
shown in the inverted orientation where the anomeric carbon C-2 is drawn on the left. Take a
moment to study the structure and identify the location of the numbered carbon atoms in each
sugar ring.

      HO       6                                             6                                                                               1
                                                HOH2C                              OH                                        HOH2C
           5         O
      H                    H                                     H       O       OH                                                              H       OH
           H                                                                                                                                         O
     4                         1                         5                                   2                                        2                          5
           OH        H                                           4               3                                                               3       4
                3   2
      OH                   OH                                H                           CH2OH                                           OH                  CH2OH
                                                                 OH              H       1                                                 OH            H   6
           H         OH

     -D-glucose in                                  -D-fructose in                                                                  -D-fructose in
     standard orientation                                standard orientation                                                                inverted orientation

In order to understand why there is such a preference of fructose for its furanose form in sucrose,
let us consider another arbitrary molecule, SucrosePyra, where the configuration of the glucose
unit remains the same (i.e. α-pyranose) but the fructose is changed from β-furanose to β-
pyranose configuration.
                                   HO       6
                                                                          HO                                         6
                                        5            O           H                               O                           OH
                                        H                            1               2           H               OH              5
                                        OH           H                                           3               4
                                            3        2
                                                                         O                                                   H
                                        H            OH                                          OH              H

                                                                 SucrosePyra .
8. Draw Sucrose and Sucrosepyra in CAChe and find their ΔHf values. Which is more

Procedure: i) First draw a cyclohexane ring. Beautify it. The chair form with all hydrogen
substituents will appear. Press Ctrl F to centre the structure on the window. Rotate it to view it as
in (I). (ii) Replace any one equatorial-hydrogen of the chair, with an oxygen atom (II) using the
select tool and “Oxygen/sp3” selected in the pull down windows at the top left corner. (iii)
Connect this oxygen to a carbon. Join this carbon to another carbon and repeat to draw a five-
membered ring. Select the whole molecule and click on Beautify/Comprehensive. (iv) Put in the
ring oxygens by highlighting the corresponding the ring carbons with the select tool and
selecting, “Oxygen/sp3”. Select the whole molecule and click on Beautify/Comprehensive.
[Warning: The structure will look very different from the structures shown here because
rings will not be flat in the models. Be sure to double check that you have drawn all the
stereocenters in each ring correctly. The easiest way to do this is to focus on only one ring
at a time and match it with the above drawn structures.] Save this file as Sucrose.csf. Now
click on “Experiment/New” in the drop down menu. In the new window which appears, choose
“chemical sample” under Property of, “optimized geometry” under Property, “PM5 geometry”
under Using. Click “Start”. Calculation will begin. The molecule’s ΔHf value will be displayed
at the end of the calculation. Record it. Close the Experiment and experiment status windows.
Follow a similar procedure to draw the Sucrose Pyra. Only difference in this case would be to
draw a six membered ring instead of a five for step (iii) above. Calculate its heat of formation.

ΔHf   (Sucrose)   =                               ΔHf   (SucrosePyra)   =

You will see that CAChe predicts sucrose to be the more stable. It is not clear (from these
calculations or to the author) why fructose adopts the furanose form exclusively in

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2. B.Schneider, F.W. Lichtenthaler, G. Steinle and H. Schiweck, Liebigs. Ann. Chem. 1985,
2443-2453; F.W. Lichtenthaler and S. Rönninger, J. Chem. Soc., Perkin Trans. 2, 1990, 1489-