Abstract: This computation study using the Gaussian software of 12 molecules (6

discrete molecules 2 conformers of each) gave one the ability to discern and visualize
why two stables conformers (global and local minimums) have a difference in molecular
energies. Furthermore 4 different computations were used (2 different methods (HF
(Hartree-Fock) and DFT (Density Functional Theory)) using 2 different basis sets (6-31(d)
and 6-311(d)) for each molecule. This gives the ability to elucidate which method and
basis set is best suitable for future computations for small to medium sized organic
molecules.

Introduction: The basis for these computations lies in the experiments done by Prof. Jik
Chin called Bioinspired Chemical Inversion of L-Amino Acids to D-Amino Acids and
Highly Stereospecific Generation of Helical Chirality by Imprinting with Amino Acids:
A Universal Sensor for Amino Acid Enantiopurity. In both of these experiments Prof.
Chin was able to racemise natural L-amino acids into D-amino acids. In the first paper,
Prof. Chin imprimed amino acids (alanine) onto 2,2-dihydroxybenzophenone; the amine
functional group of the amino acids reacted to form an imine. After the imine was formed,
the L analogue of the amino acid (now imine) was disfavoured because of steric
hindrance
1
. In this spirit, this computational experiment expands on these two papers by
using different types of computational methods (DFT and HF) and adding more side
groups on the imine (tert-butyl and phenyl). Throughout this experiment, it is expected
that the original observations of Prof. Chin would not change -- that steric interactions
would still play a crucial role in determining the formation of one enantiomer over the
other. These calculations would give one the chance to observe how much the molecular
energies change as the substituent groups get larger and also to observe how the
computational results varies by using different methods. These calculations provide
valuable information on the chirality selection rate for D-amino acids which could
possibly have profound implications for the future such as medical and synthetic
applications. Computations were used instead of experimental methods because
computational methods are cost effective and can be done when experimental methods
are unavailable.

Methods: The two computational methods used in this experiment were the Hartree-
Fock (HF) approximation and the Density Functional Theory (DFT). Hartee-Fock is the
most common ab initio method. This means that computations are derived directly from
theoretical principles with no inclusion of experimental data
10
. This is an approximate
quantum mechanical calculation. The approximations made are usually mathematical
approximations, such as simpler functional form for a function or finding an approximate
solution to a differential equation. The primary approximation is the central field
approximation. This means that the Coulombic electron-electron repulsion is taken into
account by integrating the repulsion term. This gives the average effect of the repulsion,
but not the explicit repulsion interaction. This is a variational calculation, meaning that
the approximate energies calculated are all equal to or grater than the exact energy. The
second approximation if HF calculations is due to the fact that the wave function must be
described by some mathematical function, which is known exactly for only a few one-
electron systems. The function used most often are linear combinations of Gaussian-type
orbitals exp(-ar
2
), abbreviated GTO. The wave function is formed from linear
combinations of atomic orbitals, or stated more correctly, from linear combinations of
basis functions. Because of this approximation, most HF calculations give computed
energy greater than the Hartree-Fock limit. The exact set of basis functions used is often
specified by an abbreviation, such as STO-3G or 6-311++g**
2
.

Density Functional Theory (DFT) has become very popular in recent years. This is
justified based on the pragmatic observation that is it less computationally intensive than
other methods with similar accuracy. This theory has been developed than other ab initio
methods. The premise behind DFT is that the energy of a molecule can be determined
from the electron density instead of the wave function
9
. In this formulation, the electron
density is expressed as a linear combination of basis functions similar in mathematical
from to HF orbitals. A determinant is then formed from these functions, called Kohn-
Sham orbitals. It is the electron density from this determinant of orbitals that is used to
compute the energy. Specifically, in this experiment to determine the energies of the
molecules, the type of Density Functional that was used was the B3LYP. This is a hybrid
method
2
.

The basis sets used in this experiment are described by the notations: 6-31G(d), 6-311G(d)
and 6-311G(d,p). These are called the Pople sets, and the notation means that each core
orbital is described by a single contraction of six GTO primitives and each valence shell
is described by two contractions, one with three primitives and the other with one
primitive. Furthermore, the Popl basis sets can be further expanded to include several sets
of polarization functions, f functions and so on, there has been an need for a new notation.
For example the donation 6-31G(d) means that an extra set of d functions have been
added to nonhydrogens
2
.


Results: Table 1. Energy Difference Between The Global and Local Minimums
*The energy difference seen is in Kcal/mol. Small refers to methyl group. Medium
refers to tert-butyl group. Large refers to phenyl group.

Chirality Generation

Dif. HF
small
Small 7.99
Medium 10.98
Large 5.51


Dif. HF
large
Small 8.93
Medium 10.76
Large 5.59


Dif. DFT
small
Small 5.921
Medium 12.03
Large 6.85


Dif. DFT
large
Small 6.124
Medium 12.1
Large 7.09
Epimerization

Dif. HF
small
Small -0.507
Medium -0.037
Large -1.597


Dif. HF
large
Small 1.039
Medium 3.573
Large 0.943


Dif. DFT
small
Small 1.108
Medium 2.346
Large 1.684


Dif. DFT
large
Small 1.167
Medium 2.473
Large 2.06

Chart 2: Hydrogen Bond Lengths.

HN HO HO
Avera
ge H-
Bond
Lengt
h
Differe
nce in
H-
Bond
Lenght
s
1AG 1.618 1.433
1.525
5 -0.006
1AL 1.581 1.482
1.531
5
2AG 1.615 1.457 1.536 -
0.0085
2AL 1.655 1.434
1.544
5
3AG 1.623 1.511 1.567
-
0.1265
3AL 1.748 1.639
1.693
5
1BG 1.866 1.865 1.57 1.767
-
0.1163
3
1BL 1.81 1.912 1.928
1.883
333
2BG 1.837 1.877 2.788
2.167
333
0.2773
33
2BL 1.806 1.963 1.901 1.89
2BG 1.83 1.91 1.918 1.886 0.08
3BL 1.686 1.846 1.886 1.806


Chart 3. Energy Differences Between Calculations Done with Large and Small Basis Sets
Compound Energy
[Hartree]*

HF small HF large Energy
Differenc
e HF
large -
HF small
DFT small DFT large Energy
Differenc
e DFT
large -
DFT
small
C16H14O4
N G
-
962.61015
7
-
967.99938
3
-
5.38922
7
-
973.86134
7
-
974.13236
7
-0.271020
C16H14O4
N L
-
962.59742
1
-
967.98514
4
-
5.38772
2
-
973.85191
1
-
974.12260
7
-0.270696
Energy
difference
[kcal/mol]
7.991575 8.935577 5.921442 6.124724
C19H20O4
N G
-
1079.0713
18
-
1085.0943
93
-
6.02307
5
-
1091.8012
03
-
1092.1035
00
-0.302297
C19H20O4
N L
-
1079.0538
04
-
1085.0772
39
-
6.02343
5
-
1091.7820
26
-
1092.0842
16
-0.302191
Energy
difference
[kcal/mol]
10.989944 10.764291 12.033962 12.100573
C21H16O4 - - - - - -0.314083
N G 1152.0536
09
1158.5033
49
6.44974
0
1165.5964
70
1165.9105
54
C21H16O4
N L
-
1152.0448
20
-
1158.4944
29
-
6.44960
9
-
1165.5855
53
-
1165.8992
42
-0.313689
Energy
difference
[kcal/mol]
5.514880 5.597127 6.850703 7.098293



Discussion: As seen in Prof. Chins experiment, the most important factor in determining
the energy difference between the Global and the Local minimum structure is the steric
interaction between the substituents. The steric interaction effect favours the formation of
the Global minimum molecular energy. This is seen in the nearly 8 kcal/mol molecular
energy difference between the molecules 1AG and 1AL. Molecules want to minimize the
steric interaction as much as possible because electrons clouds repel each other if they get
too close
3
. From the energy difference data one can see that the largest difference in
energies arises when the substituent is of medium size. This can be rationally explained
because smaller side groups would have a smaller electron cloud regardless of whether
(described using Newman projections eclipsed or staggered) they are pointing towards or
away from other groups in the larger molecule as a whole. For large groups such as
phenyl, their electron clouds are large and therefore would be significant steric
interaction regardless of whether the group is pointing away or toward other functional
groups. This leaves only the medium sized group (tert-butyl) as the substituent that would
result in the largest molecular energy difference between the global and the local
minimums. From this result, if one can design molecules with medium sized group it that
would increase the yield for the chirality generation experiment
2
.

In both groups of molecules seen (Chirality Generation and Epimerization), hydrogen
bonding plays a key part in the stability of molecules. Using the computationals, it is seen
that not only do the structures with the global minimum have their subtituents pointing
away from other groups to minimize steric interactions, but their hydrogen bonds lengths
are also smaller. For example this is seen in comparing molecules 1AG and 1AL, where
the global minimum structures hydrogen bonds are 0.006 shorter. Some of these
hydrogen bonds are resonance assisted hydrogen bonds and they play a key role in the
energy difference between the global and the local structures. The difference between
RAHB and ordinary hydrogen bonds is that RAHB it is caused by delocalisation around
and makes it stronger than ordinary hydrogen bonds. It has a partial covalent and
electrostatic character, and thus forms shorter distances. Contrary to common sense
where steric hindrance would lead to a higher energy, with RAHB the distance between
molecules are increased but the shorter distances of the hydrogen bonds caused through
RAHB lowers the energy
4
.

One of the goals of this experiment was to determine which computation method and
basis set would better describe reality. Because of the central field approximation, the
energies from HF calculations are always greater than the exact energy and tend to a
limiting value called the Hartree-Fock limit as the basis set is improved
5
. From this one
can see, that since the molecular energy result gained from HF calculation with the larger
basis is the better result since it gives the smaller result.

Since the foundation of computational chemistry is based around mathematical
simplifications, adding some experimental data helps enrich the data. The B3LYP
method hybrid functional is the most widely used for molecular calculations by a fairly
large margin and this was one the methods used in this experiment
2
. The molecular
energies derived from the DFT method, using both large and small basis sets yielded data
which were smaller than HF methods. Because of the tendency of HF results to be large
than actual value, one can assume that the DFT results are better than HF values in this
experiment. This is because of the accuracy of the B3LYP results obtained for a large
range of organic compounds can been observed in many other computational experiments.

Another observation when the energy differences are compared by using different basis
sets with the same molecule. The energy differences are constant between larger and
smaller basis sets for molecules that are the global and the local minimum. For example
the energy differences in Hartrees for 1AG calculations using both the smaller and the
larger basis set is 5.3. This is approximately the same for 1AL. As the molecule gets
larger the difference increases to about 6.2 and 6.4 for HF calculations. This suggests that
the result discrepancy increases as more electrons are introduced. This can be alleviated
in HF calculations by using a larger basis set, but this is not an option for DFT
calculations since the density functional is the limiting accuracy more than basis set
limitations
6
.

Conclusion: In general, ab initio calculations give very good qualitative results and can
yield increasingly accurate quantitative results as the molecule in question become
smaller. The advantage of ab inition methods is that they eventually converge to the exact
solution once all the approximations are made sufficiently small in magnitude. The
drawback of DFT calculations is that there are no systematic ways to improve the
calculations, thus making them unusable for very-high-accuracy work
8
. Because of this,
there are classes of problems not yet explored with this theory, making it all the more
crucial to test the accuracy of the method before applying it to unknown systems.
Sometimes it has been observed that the output of DFT calculations are significantly off,
and some care must be taken when using DFT results
7
. In this experiment, the molecular
energies for the same energies are not significantly different, but in order to gain the best
results the solution would be to use HF with the largest basis sets.

Works Cited:

1. J Chin. Angew. Chem. Int. Ed. 2008, 47, 8657-8660.

2. Young, David. Computational Chemistry: A Practical Guide for Applying Techniques
to Real-World Problems. Wiley, 2001.

3. Bloch, Daniel. Organic Chemistry Demystified. Mc-Graw Hill, 2006.

4. P Gilli. J. Am. Chem. Soc. 2000, 122, 10405-10417.

5. E. Clementi. J. Phys. Chem. 1985, 89, 4426-4436.

6. Rogers, Donald. Computational Chemistry Using the PC. Wiley-Interscience, 2003.

7. Jensen, Frank. Introduction to computational chemistry. Wiley, 2007.

8. A Cohen. Science. 2008, 38, 792-794.

9. M Orio. Photosynth Res. 2009, 102, 443453

10. Cramer, Christopher. Essentials of computational chemistry. Wiley, 2005.