Ab initio Study on Benzoin Condensation Catalysed by Alagebrium

Ab initio Study on Benzoin Condensation Catalysed by Alagebrium in order to Test for Alagebrium’s Potential as a Thiamine Supplement
Dhia Azzouz1, Natalie J. Galant2, Bela Viskolcz3, Imre G. Csizmadia1,3
1. Department of Chemistry, 2. Department of Biophysics, University of Toronto, Ontario
3. Department of Chemistry and Chemical Informatics, University of Szeged, Hungary
Numerous enzymes in the body are assembled with the help of thiamine,
also known as vitamin B1, and are involved in many critical biochemical
reactions in the body [1]. Examples of biochemical reactions include the
synthesis of neurotransmitters, nucleic acids, fatty acids, steroids as well
others [1].
Thiamine deficiency often leads to increased blood flow in vasculature,
heart failure, sodium and water retention in the body and a neurological
disorder known as Wernicke–Korsakoff syndrome (WKS) [1].
Reaction Mechanisms
Results
500
Figure 2: Structures of benzaldehyde (left) and 2-hydroxy-1,2-diphenylethanone
(Benzoin) (right).
T1
Wernicke’s Encephalopathy and Korsakoff’s Psychosis
T4
0
0
T3
T2
2
3
4
5
T4
T5
6
-1000
-1500
8
9
-2000
-3000
T7
-3500
T8
Reaction Progress
T8
Figure 3: Schematic of benzoin condensation catalyzed by thiamine.
Relative Energy (kJ/mol)
T6
A1
A2
1
2
0
-500
3
4
5
A4
A5
6
7
8
9
A7
A8
A3
-1000
-1500
-2000
A6
-2500
-3000
-3500
-4000
Figure 6: Gibbs Free energy changes during benzoin condensation
catalysed by Alagebrium. Values include all molecules involved. Labels on
the curve correspond to the steps of the reaction mechanism in Figure 4.
A7
Figure 1: Structures of thiamine (left) and Alagebrium (right).
A5
A6
Relative Energy (kJ/mol)
A2
15
A8
Figure 4: Schematic of benzoin condensation catalyzed by Alagebrium.
1. Martin, P. R., Singleton, C. K., & Hiller-Sturmhofel, S. (2003). The role of
thiamine deficiency in alcoholic brain disease. Alcohol Research and
Health,27(2), 134-142.
3. Nagendrappa, G. (2008). Benzoin condensation. Resonance, 13(4), 355-368.
10
T2 - A2
5
0
0
1
T1 - A1
2
3
T7 - A7
4
T4 - A4
5
6
7
8
T8 - A8
9
-5
-10
-15
Methods
T6 - A6
T3 - A3
References
2. Coughlan, M. T., Forbes, J. M., & Cooper, M. E. (2007). Role of the AGE
crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney
international, 72, S54-S60.
Difference in Energy between Thiamine and
Alagebrium as Catalyst
A3
Should the in vitro experiment lead to the desired results, in vivo studies
could begin to test whether Alagebrium could replace thiamine
pyrophosphate as both share the carbine functional group that is
involved in the catalytic reactions. Other future possibilities include
adding functional groups such as an alcohol in hopes of promoting the
phosphorylation of the drug in the body to further promote TPP-like
activities.
Reaction Progress
A1
A4
Future Directions
The next step would be to compare activation energies of the two
reaction mechanisms and to perform an in vitro experiment of benzoin
condensation using Alagebrium as catalyst.
Benzoin Condensation Catalysed by
Alagebrium
0
The largest difference between the parallel steps in benzoin
condensation catalysed by thiamine and benzoin condensation catalysed
by Alagebrium was 10.07 kJ/mol (2.41 kcal/mol) (Figure 7). The
differences are not significantly large which suggests that benzoin
condensation catalysed by Alagebrium can potentially take place in
physical settings. The differences also suggest that non-carbine functional
groups have little effect on the reaction such as via steric hindrance.
The calculations don’t compare the rates for the two reactions. To
determine the rate for both reactions, activation energies must be
calculated.
T6
-2500
20
The molecules were constructed in Gaussview 5.0 and studied in gaseous
states using the DFT method at the B3LYP/6-31G(d) level of theory using
the Gaussian 09 program.
7
T3
T7
Benzoin condensation, an in vitro experiment utilising thiamine as
catalyst, mimics the mechanism of thiamine diphosphate-dependant
enzymatic reactions in biological systems [3]. Thiamine is converted in
cells to thiamine diphosphate [1].
The reaction mechanisms of benzoin condensation catalyzed by thiamine
and benzoin condensation catalyzed by Alagebrium are illustrated in
Figure 3 and Figure 4, respectively.
1
-500
500
Alagebrium was a drug traditionally tested for the purpose of breaking
the crosslinks caused by advanced glycation end-products [2]. In this
experiment, Alagebrium, which contains the carbine functional group
which is responsible for the reactions that thiamine diphosphate
undertakes, was analysed computationally in a benzoin condensation
reaction to determine its potential use as a thiamine supplement.
T2
Figure 5: Gibbs Free energy changes during benzoin condensation
catalysed by thiamine. Values include all molecules involved. Labels on
the curve correspond to the steps of the reaction mechanism in Figure 3.
When WKS is suspected in a patient, a high parenteral thiamine dose is
administered. However, patients are often at risk of anaphylactic
reactions associated with administration of parenteral thiamine [1].
T5
T1
-4000
WKS is composed of Wernicke’s encephalopathy (WE) and Korsakoff’s
psychosis (KP) [1]. The symptoms of WE include confusion, paralysis of
nerves responsible for eye movement and difficulty to coordinate
movements [1]. The symptoms of KP include odd behaviours, inability to
remember old information and reduced ability to absorb new
information [1].
Alagebrium
Conclusion
Benzoin Condensation Catalysed by
Thiamine
Relative Energy (kJ/mol)
Introduction
T5 - A5
Reaction Progress
Figure 7: Differences in Gibbs Free Energy between the parallel steps (T#
and A#) of benzoin condensation by thiamine and benzoin condensation
by Alagebrium. Labels on the curve correspond to the steps of the
reaction mechanisms in Figure 3 and Figure 4.
Acknowledgements
I would like to thank the Department of Chemistry and the Research
Opportunity Program at the University of Toronto for providing the
research opportunity, Natalie J. Galant for her continuous support, Craig
Yu for his invaluable advice, Johnson Li and Jay Lee for their technical
help, and the University of Szeged for providing the software to run the
calculations and a cluster on which to run them.
Quantum Chemical study on the concerted addition reaction mechanism of HF to C2H4
Dohyun Kim, Natalie J. Galant, Imre. G. Csizmadia
1. Department of Chemistry, University of Toronto, Ontario
2. Department of Medical Biophysics, University of Toronto, Ontario
Result and Discussion
Introduction
Fluorocarbon based molecules are more
chemically and thermally stable than
hydrocarbons due to strong covalent bond in
between fluorine and carbon. Pharmaceuticals
use this various reactivity of C-F bond to create
[1,2]
a drug such as flunitrazepam.
CH2=CH2 + H-F
Ethene
Hydrogen Fluoride
CH3-F
Fluoroethane
Figure 2. IRC graph of gas phase (left) and in CCl4 solvent (right) in B3LYP6 model in concerted reaction
Transition state of fluoroethane in CCL4 solvent is more negative than the transition state in gas phase. It shows that formation of fluoroethane is more
favorable in solvent than in gas.
-470097.2 0
300
Method
To find the optimal structure of the reactants,
transition state and product, B3LYP6-31G[21] level of
theory was performed on Gaussview.
Formation of fluoroethane was done in both of gas
and CPCM CCl4 solvent phase. In gas phase, bond
length of C-F was set to 1.8, and dihedral angle was
set to 89°. In CPCM, CCl4 1.9 and 89°.
In order to compare between concerted reaction
and step-wise reaction, different bond length of H-F
was used. In step-wise reaction, bond length
between H-F was longer than C-F.
100
150
200
250
300
350
400
450
-470099.2
250
-470101.2
200
Total Energy (kJ/mol)
-470103.2
150
-470105.2
100
Figure1. Nucleophilic hydrogen fluoride attacks the
ethene, eliminating double bond and forming
Fluoroethane
50
50
-470107.2
0
-470109.2
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
-470111.2
-50
Figure 3. Energy diagram of hydrogen fluoride and
ethene producing fluoroethane in B3LYP6 model
degree. (Red in CCl4, blue in gas phase, step-wise reaction)
-470113.2
Scan Coordinate
Figure 4. scan coordinate of product (Fluoroethane) in kJ/mol From 50 degree to 410
Conclusion
In concerted reaction, CCl4 solvent required 240.44kJ/mol of activation energy to proceed the reaction, and in
gas phase, 237.16kJ/mol was required.
On the other hand, in step-wise reaction, activation energy of molecule in CCl 4 solvent was 239.84kJ/mol and gas
phase was248.05kJ/mol. Formation of fluoroethane was significantly more stable in CCl 4 solvent than molecule in
gas phase. It suggests that step-wise reaction is more solvent dependent than concerted reaction.
References
1. Vogel, A. I.; Leicester, J.; Macey, W. A. T., "n-Hexyl Fluoride", Org. Synth.; Coll. Vol. 4: 525
2. Le Bars, D. (2006). "Fluorine-18 and Medical Imaging: Radiopharmaceuticals for Positron Emission
Tomography". Journal of Fluorine Chemistry 127 (11): 1488–1493.
3. Stéphane Caron, Robert W. Dugger, Sally Gut Ruggeri, John A. Ragan, and David H. Brown Ripin (2006). "Large-Scale
Oxidations in the Pharmaceutical Industry". Chemical Reviews 106 (7): 2943–2989.
4. William R. Dolbier, Jr. (2005). "Fluorine Chemistry at the Millennium". Journal of Fluorine Chemistry 126 (2): 157.
5. Pichika Ramaiah, Ramesh Krishnamurti, and G. K. Surya Prakash (1998), "1-trifluoromethyl)-1-cyclohexanol", Org.
Synth.: 232
Acknowledgement
I would like to thank the Department of chemistry
and Research Opportunity program 299 at
University of Toronto for giving me opportunity to
participate in this research project.
Quantum Chemical Study on the Addition Reaction of Water to Carbon Monoxide Generating
Various Isomers
Lie Yun
1
Kok ,
Natalie J.
2,3
Galant ,
Bela
3
Viskolcz ,
Imre. G.
1,3
Csizmadia
1. Department of Chemistry, University of Toronto, Ontario
2. Department of Medical Biophysics, University of Toronto, Ontario
3. Department of Chemistry and Chemical Informatics, University of Szegad, Hungary
Results
Introduction
• An NMR spectroscopic study showed evidence of
Methods
•Reactants, products and transition states were
optimized with B3LYP/6-31G(d) level of theory in
vacuum and water (CPCM model)
(a)
formic acid as the intermediate of the water-gas shift
reaction1, but the addition reaction of water to carbon
monoxide can produce a few different constitutional
isomers: formic acid (HCOOH), dihydroxycarbene
(HOCOH) and dioxirane (CH2 (O2)) .
Formic acid
trans-HCOOH
Dihydroxycarbene
cis,cis-HOCOH
•Input files of each reactant, product and transition
state were modified manually for calculations in
G3MP2B3 level of theory
•Free energy values for each molecule in both vacuum
and solvent were obtained in Hartrees and converted
to kJ/mol (1 Hartree = 2625.5 kJ/mol)
Dioxirane
•A potential energy surface scan was performed on
the 2 dihedral angles around the carbon of HOCOH
with 24 steps of 15 degrees.
CH2(O2)
cis,trans-HOCOH
Conclusion
(b)
-
cis-HCOOH
-
-
-
trans,trans-HOCOH
-
-
-
-
-
-
• Formic acid have several useful applications in the
industries but dioxirane is found to contribute to air
pollution2, thus it is important to determine how
likely each isomer will be produced.
• Formation of HCOOH conformers is spontaneous in
B3LYP/6-31G(d) calculations but not spontaneous in
G3MP2B3 calculations. Both levels of theory show that
trans-HCOOH is a more stable product compared to
cis-HCOOH. This reaction is exothermic.
•An ab initio study will be useful for understanding
the thermodynamic stability of the products in this
reaction. This will help to determine the means of
application of this reaction.
• To compare the thermodynamic stability of each
constitutional isomer and conformer formed in the
reaction
• To determine the spontaneity of the reaction in
vacuum and in water
References
1. Yoshida K. , Wakai C., Matsubayashi N., Nakahara M. (2004). NMR
Spectroscopic Evidence for an Intermediate of Formic Acid in the
Water−Gas−Shift Reaction. J. Phys. Chem. A. 108 (37):7479–7482.
2. Hu, S., Lu, S., Wang, X. (2004). Theoretical Investigation of Gas-Phase Thermal
Reactions between Carbon Monoxide and Water. J Phys Chem. A. 108(40): 84858494.
D2
Potential energy surface scan of HOCOH
Relative energy (kJ/mol)
• To calculate the thermodynamic properties of the
reactants, products and transition states in B3LYP/631G(d) and G3MP2B3 levels of theory
Figure 1 Energy profile for the addition reaction of water to carbon monoxide in vacuum and water. Calculations were
done in (a) B3LYP/6-31G(d) and (b) G3MP2B3 levels of theory with relative energy values given in kJ/mol. TransHCOOH is found to be the most stable product and CH2(O2) is the least stable.
Relative energy (kJ/mol)
Objective
• HCOOH was found to be the most stable product
and its formation has the lowest activation energy
barrier, so this reaction will occur most rapidly.
Therefore, HCOOH should be the major product of
the addition of water to carbon monoxide. This
supports the NMR study that formic acid is most
likely the intermediate in a water-gas shift reaction.
D1
cis, cis-HOCOH
• Formation of CH2(O2) and the 3 conformers of
HOCOH are not spontaneous and are endothermic.
cis, trans-HOCOH
D2
• CH2(O2) is the least stable product and its formation
has the highest activation energy barrier, thus the
reaction will be very slow and it is the least likely to be
formed. Since a high amount of energy is required to
form CH2(O2), the production of this isomer may not
be a concern unless the reaction occurs under
conditions that favor the formation of CH2(O2).
•The cis, cis conformation of HOCOH is the least
favorable compared to the other 2 conformers.
Acknowledgement
D1
trans, trans-HOCOH
Figure 2 Potential energy surface scan of dihydroxycarbene (with energy values relative to the smallest value in
kJ/mol) around the Ψ and Φ dihedral angles of HOCOH. The minimum for the cis, cis-conformer appears to be higher
in energy compared to the minima of the other two conformers.
I would like to thank Craig Yu, Jay Lee, Johnson Li and Alicia Park for
their help and guidance. I would also like to thank the Department of
Chemistry and ROP299 director for providing the opportunity to do
research, as well as University of Szegad for allowing calculations to
be run with their software.
Ab ini&o study of R and S 2-­‐keto-­‐3-­‐methylvaleric acids forma&on in Maple Syrup Urine Disease 1,3
3
, Bela Viskolcz , Imre. G. Csizmadia
Nidaa Rasheed1, Natalie J. Galant2
3. 
Introduc)on 1.  Department of Chemistry, University of Toronto, Ontario 2.  Department of Medical Biophysics, University of Toronto, Ontario Department of Chemistry and Chemical Informa&cs, University of Szeged, Hungary Results and Discussion Maple Syrup Urine Disease • 
Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disease • 
Makes the urine of the affected individual smell sweet like maple syrup and is caused by a deficiency of the branched-­‐chain a-­‐keto acid dehydrogenase enzyme complex [1] • 
Causes accumula)on of the branched chain amino acids (leucine, isoleucine and valine) and their toxic-­‐by products (keto-­‐acids) in the blood and urine [2] • 
Symptoms include ketoacidosis, hypoglycemia, apnea, coma, mental retarda)on, and fibrous gliosis of the brain’s white maLer [1] Conclusion Forma)on Reac)on 1: (S) 2-­‐keto-­‐3-­‐methylvaleric acid to (E) 2-­‐hydroxy-­‐3-­‐methylpent-­‐2-­‐enoic acid • 
140 • 
Rela)ve Free Energy (kJ/mol) 120 Molecular Structure and Biological Synthesis • 
High level of L-­‐alloisoleucine and the keto-­‐acids are found in MSUD [3] • 
L-­‐alloisoleucine (S2, 3R), a diastereoisomer of L-­‐isoleucine (2S, 3S), and the two keto-­‐acids (S) and (R) 2-­‐keto-­‐3-­‐methylvaleric acid (KMVA) are normal cons)tuents of human plasma [4] • 
The chiral center of KMVA has been proposed to racemize through non-­‐enzyma)c keto-­‐enol tautomerism to yield R and S isomers (Figure 1) [5] • 
100 The overall thermodynamic property of the keto-­‐enol tautomerism reac)on between (S) to (R)-­‐KMVA was found to be exergonic with a posi)ve entropy change, thus making it favorable in the forward direc)on Thermochemical data shows that the (R)-­‐KMVA is very stable; therefore, making Reac)on 2 highly favorable The use of hydronium was shown (Figure 6) to stabilize the carboxylic acid and to act as a type of catalyst in order to undergo the reac)on 80 60 40 20 0 -­‐20 Reac)on Coordinate -­‐40 Figure 3. Forma)on Reac)on 1 The reac&on profile of the keto-­‐enol tautomerism of Reac&on 1 (S) 2-­‐keto-­‐3-­‐methylvaleric acid to (E) 2-­‐
hydroxy-­‐3-­‐methylpent-­‐2-­‐enoic acid. This is an exergonic reac&on with a change value of -­‐12.58 kJ/mol. However, there is a high rate-­‐determining transi&on state, which accounts for the slow forma&on of the enol. Forma)on Reac)on 2: (E) 2-­‐hydroxy-­‐3-­‐methylpent-­‐2-­‐enoic acid to (R) 2-­‐keto-­‐3-­‐methylvaleric acid 200 100 Rela)ve Free Energy (kJ/mol) 0 Figure 1. Suggested reac&on of the forma&on of L-­‐alloisoleucine from L-­‐isoleucine. Methods B3LYP/6-­‐31G (d) Gaussian 09 (G09) program was used to calculate the op)mal structures (Figure 2) [6] G3MP2B3 Used a higher level of theory to yield more accurate results and DFT was used to calculate thermodynamic proper)es [6] Results Gibbs free energy and enthalpies of the structures were obtained, using conversion factor 1 Hartree = 2625.49963 kJ/mol -­‐100 Figure 6. Op&mized structure of both Reac&on 1 and 2 using Gaussian 09 under the B3LYP level of theory. -­‐200 Future Direc)ons -­‐300 -­‐400 • 
-­‐500 • 
-­‐600 Reac)on Coordinate -­‐700 • 
Figure 4. Forma)on Reac)on 1 The reac&on profile of the keto-­‐enol tautomerism of Reac&on 2 (E) 2-­‐hydroxy-­‐3-­‐methylpent-­‐2-­‐enoic acid to (R) 2-­‐keto-­‐3-­‐methylvaleric acid. This is an exergonic reac&on with an overall rela&ve change value of -­‐615.14 kJ/mol., as the product is much more stable than the reactant. 3D Poten)al Energy Surface Scan of (R) 2-­‐keto-­‐3-­‐methylvaleric acid -­‐1208575.5 -­‐1208580.8 E (kJ/mol) -­‐1208586.0 -­‐1208591.3 -­‐1208596.5 X1 -­‐1208601.8 X2 -­‐1208607.0 -­‐1208612.3 -­‐150 -­‐100 X1 Figure 2. Suggested chemical formulae for the forma&on of R-­‐2-­‐keto-­‐3-­‐methylvaleric acid from S-­‐2-­‐keto-­‐3-­‐methylvaleiric acid via the E -­‐2-­‐hydroxy-­‐3methylpent-­‐2-­‐enoic acid. -­‐50 0 50 100 -­‐100 150 -­‐150 -­‐50 0 50 100 150 X2 Figure 5. 3D Poten)al Energy Surface Scan The poten&al energy surface scan was done on the dihedral angle between C1 to C4 (X1) and between C3 to O6 (X2), while the angle between C3 to C4 was fixed. The scan revealed that, in the lowest energy conforma&on, the carbon chain ( C1 to C3) is spread out in a planar-­‐like structure and that the carboxylic acid group is farthest away from the ketone group. • 
To get a greater understanding of these calcula)ons, water phase calcula)ons should be completed Aside from using hydronium, deuterium (D2O) should be used as a more accurate reactant since the normal pH of plasma is 7.4 The reac)on should be calculated using a very basic solvent to see if the forma)on of the enol can become an exergonic reac)on, thus, to see if this is a cataly)c reac)on Another reac)on using (Z)-­‐enol as the intermediate should also be calculated in order to compare if this mechanism is truly the most favorable References 1.  Menkes. J. H., Hurst, P. L., Craig, J. M. (1954) New syndrome: progressive infan)le cerebral dysfunc)on. Pediatrics. 14, 7 – 462 2.  Danner, D.J., and Elsas, L. J. II (1989) The Metabolic Basis of Inherited Disease: Disorders of Branched Chain Amino Acid and Keto Acid Metabolism (Seriver, C. R., Baudet, A. L., Sly, W. S., and Valle, D., eds) 6th Ed. McGraw-­‐Hill, New York, pp. 671-­‐692 3.  McKusick V.A. (1994) Mendelian Inheritance in Man, 11th Ed. John Hopkins University Press, Bal)more 4.  Mamer, O.A., Montgomery, J.A., Taguchi, V.Y. (1980). Origin of the two peaks for 2-­‐keto-­‐3-­‐methylvaleric acid produced by the oxida)on of the keto acids occurring in maple syrup urine disease. J Chromatogr 182:221–225 5.  Meister, A., White, J. (1951) Growth response of the rat to the keto analogues of leucine and isoleucine. J Biol Chem 191:211–216 6.  Becke, A. D. (1993). Density-­‐func)onal thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648-­‐5652 Acknowledgement I would like to thank the Department of Chemistry and the Research Opportunity Program (ROP299) at the University of Toronto for providing me the opportunity to undertake this research project. Furthermore, I would like to thank the University of Szeged for providing the somware enabling the energy calcula)ons, as well as Craig Yu, Johnson Li, and Jay Lee for general support and technical assistance. Quantum chemical study on the concerted addition reaction
mechanism of H2O to CH2O
PeiXuan Chen1,2, Natalie J. Galant3, Imre G. Csizmadia4 and Béla Viskolcz4
1.  Department of Physiology, Faculty of Arts and Science, University of Toronto, Canada
2.  Department of Molecular Genetics, Faculty of Arts and Science, University of Toronto, Canada
3.  Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Canada
4.  Department of Chemical Informatics, Faculty of Education, University of Szeged, Hungary
ABSTRACT
METHODOLOGY
•  Computational studies have been done on the concerted
addition of water (H2O) to formaldehyde (CH2O) to produce
methanediol (CH2(OH)2).
•  Plausible mechanisms were identified and compared using
energy scans to show which one is more likely to proceed.
Determined that the reaction is only favourable when
solvation is taken into account.
•  The conformation behavior of formaldehyde was also
studied to mimic the anomeric effect of carbohydrate
molecules.
•  Initial structures of CH2O, H2O and CH4O2 were
Preparation generated using Gaussview5.0.
of Input •  Gaussian09 input files prepared from structures.
Files
•  Basic geometric optimization of molecules at
B3LYP/6-31G(d) level of theory.
•  Thermodynamic properties (ΔHo, ΔSo, ΔGo)
Calculations calculated with G3MP2B3 model chemistry.
INTRODUCTION
•  Formaldehyde (CH2O) is an organic toxin produced and
stored endogenously in the human body. It undergoes
addition reaction with water (H2O) to form a less toxic
product – methandiol (CH2(OH)2). Studies on the
mechanism of this addition reaction is beneficial to prevent
development of formaldehyde-related diseases, such as
cancer.
OH
HO
O
+
C
H
O
H
H
CH2O
H2O
Analysis
Manifestation of the anomeric effect:
•  Thermodynamic data tabulated to generate energy
scans and diagrams.
•  Plotted energy vs. reaction progress graphs to
analyze energy progression.
•  2D Potential Energy Surface Scan generated from
Gaussian09 to analyze stereo-electronic effect in
molecules.
RESULTS
CH2(OH)2
Anomeric effect representation and methanediol as analog for studying carbohydrate chemistry.
• Initial addition of water to formaldehyde was unsuccessful.
This showed that such assumed reaction is not a favourable
one. Thermodynamic data showed the product, methanediol,
is unstable compared to the reactants alone. Therefore the
product itself must be stabilized for the reaction to take
place.
• Instead of one water molecule, three water molecules are
needed. One for reacting with methanediol, two more for
solvation and thus stabilization of the product.
• Presence of geminal hydroxyl groups in methanediol
allows it show the anomeric effect. This is confirmed by the
energy scan of its conformers. The anti-conformation, which
should have the most stability in most tetrahedral molecules,
manifests as an energy maxima.
• Relation between methanediol’s anomeric effect and its
instability can be explored to explain the unfavourable
addition of one water molecule to formaldehyde.
• Further investigations on the effect of the anomeric effect
has on methanediol’s reactivity, molecular behavior and
geometrical conformation can be studied to understand
carbohydrate chemistry.
H
•  Formaldehyde is also known as monose, the simplest
carbohydrate. Formaldehyde’s structural stability is largely
affected by the presence of the oxygen and the two lone
pair electrons associated with it. This effect is known as the
anomeric effect, a type of stereo-electronic disturbance
manifested by presence of heteroatoms in the molecular
structure. Conformational studies on small molecules such
as formaldehyde can be beneficial to understanding certain
chemical features of carbohydrates, which make up a
major part of metabolic reactions that are essential for life.
CONCLUSION
FUTURE DIRECTIONS
C
H
H
• Methanediol is
stabilized by
solvation when
water
hydrogenbonds with
atoms in its
structure.
REFERENCES
• Conformational PES Scans of methanediol
[1] Wolfe, L.M. Tel, M.A. Robb and I.G. Csizmadia, (1973) The Gauche Effect.
A Study of Localized Molecular Orbitals and Excited StateGeometries in
FCH2-OH. Journal of American Chemical Society. 95: 4863 - 4870
[2] Wolfe S., Tel L.M., Rauk A. and Csizmadia I.G., (1971). A Theoretical
Study of the Edward-Lemieux Effect (the Anomeric Effect). The
Stereochemical Requirements of Adjacent Pairs and Polar Bonds. Journal of the
Chemical Society. 136 – 145.
[3] Kumpf R.A. Damewood J.R., (1989). Interaction of Formaldehyde with
Water. Journal of Physical Chemistry. 93: 4478 – 4486
[4] Ha T.K. Makarewicz J. Bauder A., (1993). Ab Initio Study of the WaterFormaldehyde Complex. Journal of Physical Chemistry. 97: 11415 – 11419
ACKNOWLEDGEMENTS
We would like to thank Department of Chemistry at University of Toronto and
Department of Chemical informatics and University of Szeged for providing
the resource and support for this project. Many gratitude to the ROP299
program offered by the University of Toronto for providing the opportunity for
this project. Special thanks Craig Yu, Jay Li, Alicia Park, Alice Xu and
Johnson Li for providing the basic knowledge of computational theory.
Ab Ini'o Study of the Anomeric Effect In Fluoromethanol and AddiConal CalculaCons A Model for the Anomeric Effect Saad Khan , Natalie J. Galant , Bèla Viskolcz , Imre G. Csizmadia 1
2
3
1,3
Department of Chemistry, Faculty of Arts and Science, University of Toronto, Canada1 Department of Medical Biophysics, University of Toronto, Canada2 Department of Chemical InformaAcs, Faculty of EducaAon, University of Szeged, Hungary 3 •  The Anomeric Effect is observed in molecules, when
two heteroatoms are joined to the same carbon. To
simplify, it is seen in molecules with X-C-Y central
atoms and arises due to the carbon being attached
to molecules with lone pairs of electrons.
•  The phenomenon is also referred to as the gauche
effect. The reason is that in ethanol the two
gauche conformers are of higher energy and the
anti conformation is a global minimum.
•  However, the opposite is observed in
Fluoromethanol, as the anti conformer becomes a
maximum. The molecule serves as a model for the
Anomeric Effect. Previous studies done on the
molecule utilized less reliable methods.
Table 1 – B3LYP & G3MP2B3 Energy and Enthalpy Values Figure 2: G3MP2B3 Reac/on Coordinate of the Addi/on of Hydrogen Fluoride to Formaldehyde Non-­‐Solvated Condi/ons Figure 1: Fluoromethanol – Conformer Energy vs Dihedral Angle Figure 3: B3LYP Reac/on Coordinate of the Addi/on of Hydrogen Fluoride to Formaldehyde Non-­‐Solvated Condi/ons •  This study analyzed the reaction between
Formaldehyde and Hydrogen Fluoride, and the
energetic stabilities of the conformers of the
product.
• 
Utilizing the B3LYP level of theory it was
observed that the addition of Hydrogen
Fluoride to Formaldehyde leads to a reaction
which is exothermic and exergonic under
solvated and non-solvated conditions.
• 
However when we analyzed the results
provided by the G3MP2B3 level of theory it
was seen that the reaction is exothermic and
endergonic under solvated and non-solvated
conditions.
• 
The results of the scan show that the anticonformation of Fluoromethanol occupies an
energy maximum. Additionally the two
gauche-conformations are the two energy
minima .
[1] S. Wolfe, L.M. Tel, M.A. Robb, and I.G. Csizmadia, (1973) The Gauche
Effect. A Study of Localized Molecular Orbitals and Excited State Geometries
in FCH2-OH. Journal of the American Chemical Society. 95: 4863-4870
[2] D. Ferro-Costas, A. Vila, and R. A. Mosquera, (2013). Anomeric Effect in
Halogenated Methanols: A Quantum Theory of Atoms in Molecules Study. The
Journal of Physical Chemistry. 117: 1641 – 1650.
•  Structures of the reactants, product, and
transition state were generated using Gaussview
and Gaussian09 input files were prepared.
Figure 4: G3MP2B3 Reac/on Coordinate of the Addi/on of Hydrogen Fluoride to Formaldehyde Solvated Condi/ons Figure 5: B3LYP Reac/on Coordinate of the Addi/on of Hydrogen Fluoride to Formaldehyde Solvated Condi/ons [4] S.Wolfe, L.M. Tel, A. Rauk, and I.G. Csizmadia, (1971). A Theoretical
Study of the Edward-Lemieux Effect (the Anomeric Effect). The
Stereochemical Requirements of Adjacent Pairs and Polar Bonds. Journal of
the Chemical Society. 136 -145.
•  The reaction was analyzed via B3LYP & G3MP2B3
levels of theory, under solvated and non-solvated
conditions. The reaction coordinate graphs for the
Gibbs Free energy were plotted. Additionally, the
Total Energy, Enthalpy and Gibbs Free Energy for
the reactions were calculated.
•  Additionally, a 1D scan was utilized to measure the
energy at every 30 degrees change in the dihedral
angle of Fluoromethanol.
RESEARCH POSTER PRESENTATION DESIGN © 2012
www.PosterPresentations.com
[3] G. R. J Thatcher, (1993). The Anomeric Effect and Associated
Steroelectronic Effects. ACS Symposium Series. 539
[5] H.Roohi, and A. Ebrahimi, (2005). Anomeric Effect and rotational barrier
in fluoromethanol: A theoretical study. Journal of Molecular Structure. 726:
141 -148.
Figure 6: Enthalpy Under Solvated Condi/ons Figure 7: Enthalpy Under Non-­‐Solvated Condi/ons We would like to thank the Department of Chemistry and the Research Opportunity Program (ROP299) for facilita/ng this research project. We would also like to thank Craig Yu, Johnson Li and Jay Lee for constantly suppor/ng us and providing technical assistance. We would also like to thank the University of Szeged for providing the soeware which enabled us to perform our calcula/ons. Ab initio Study of Aminomethanol
From the Reaction of Formaldehyde and Ammonia and the Observed Anomeric Effect
Vivian Xie, Natalie J. Galant, Béla Viskolcz, Imre G. Csizmadia
Department of Chemistry, University of Toronto
Department of Medical Biophysics, University of Toronto
Department of Chemical Informatics, University of Szeged
Introduction
Results
Energy Graphs
The proposed reaction mechanism formation of aminomethanol from the
reaction between formaldehyde and ammonia is as follows:
Figure 1 Gas Phase Aminomethanol Formation at G3MP2B3 level of theory
Figure 2 Gas Phase Aminomethanol Formation at B3LYP/6-31G(d) level of
theory
Gas Phase Formation of Aminomethanol
Gas Phase Aminomethanol Formation
-448420
-448840
Biological Significance of Aminomethanol:
• Reaction between formaldehyde and ammonia create many intermediates that
can produce biological molecules i.e sugars, nucleobases, amino acids etc. 1
• Seven amino acids formed from the reaction of formaldehyde and ammonia2.
• Aminomethanol is an intermediate that can form interstellar glycine in a
reaction with a protonated form of itself with formic acid3.
• Investigation of these precursors to biologically significant molecules could give
insight to the formation of molecules such as amino acids in other conditions
outside of biology (interstellar research of biological compounds).
-448860
-448460
Standard Gibbs Free Energy (kJ/mol)
Relative Standard Gibbs Free Energy (kJ/mol)
-448440
-448480
-448500
-448520
-448540
-448560
-448580
-448600
-448920
-448940
-448960
-448980
-449000
167.05 kJ/mol
-449040
Reaction Progress
9.73 kJ/mol
Reaction Progress
Figure 3 Solvated Aminomethanol Formation at G3MP2B3 level of theory
Figure 4 Solvated Aminomethanol Formation at B3LYP/6-31G(d) level of
theory
Solvation Formation of Aminomethanol
Solvation Formation of Aminomethanol
-448480
-448880
-448500
-448900
-448920
-448520
Standard Gibbs Free Energy (kJ/mol)
Standard Gibbs Free Energy (kJ/mol)
-448900
-449020
-448620
-448640
-448540
-448560
-448580
-448600
-448620
150.53 kJ/mol
-448640
Method
-448880
12.40 kJ/mol
-448660
Reaction Thermodynamics
• Calculations carried out at standard temperature and pressure (298 K and 1 atm). In
both phases, reaction was non-spontaneous (positive ΔG value), shown in all Figures 1,
2,3, and 4.
• Exothermic (negative ΔH) but more ordered (negative ΔS)
• Studies have found the reaction to occur in interstellar ice and cometary ice4, another
studies found the reaction to be spontaneous at lower temperatures (around 100K)5.
-448940
-448960
-448980
-449000
-449020
-449040
152.05 kJ/mol
-449060
-449080
Reaction Progress
17.71 kJ/mol
Gas Phase Thermodynamic Calculations
Solvation Thermodynamic Calculations
Conformational Stability
• Figure 5: Rotation around C-O dihedral. Global minima at -60 and 60 degrees. Global
maxima at -130 and 130 degrees. Local minima at -180 and 180 degrees. Local
maxima at 0 degrees.
• Figure 6: Rotation around C-N dihedral. Global minima at -60 and 60 degrees. Global
maxima at -180 degrees. Local minima at 180 degrees. Local maxima at 0 degrees.
• Figure 7: 2D scan with both C-O and C-N rotations, showing the total energy of
molecule at different conformations.
Reaction Progress
Conclusion
Potential Energy Surface Scans
• Create molecules using Gaussview Program
• Gaussian 09 Calculation Setup:
DFTB3LYP/6-31G(d) level of theory
-171.0145
0
10
15
20
25
30
35
-171.002
40
0
5
10
15
20
25
30
35
40
-171.004
-171.015
-171.006
-171.0155
Energy (Hartree)
-171.008
Energy (Hartree)
• Use input files from B3LYP calculations,
manually set Gaussian 09 setup: G3MP2B3 level
of theory
• Find energies for all molecules, graph using Excel
5
• Reaction mechanism through proposed transition state plausible at low temperatures
(not at STP).
• Non-spontaneity of reaction in this investigation possibly due to unfavourable
conditions (high temperature 298 K)
• Thermodynamics of solvated forms suggest mechanism more likely to occur than
molecules in gas phase (more research must be done in this area before conclusively
saying anything
• Different models to explain generalized anomeric effect in aminomethanol: Dipole
interaction (repulsions between dipole of O-H and C-N destabilize anti conformation),
Charge delocalization (stability of gauche conformation due to delocalized lone pair on
nitrogen) 6. Both models accepted depending on molecular system considered.
-171.016
-171.0165
-171.01
-171.012
References
-171.014
-171.017
-171.016
-171.0175
• Potential Energy Surface Scans: Gaussview to
create molecule
• Calculation Setup: DFT  B3LYP/6-31G level
of theory
• Calculation and Potential Energy Surface Scans
obtained to create a 2D graph and two 1D graphs
• Graphs obtained on Gaussview
• Most stable conformations deduced from energy
scans
-171.018
-171.018
-171.02
Scan Coordinate
Figure 5 PES scan with rotation about C-O bond
Scan Coordinate
Figure 6 PES scan with rotation about C-N bond
Figure 7 2D PES scan
1. Delidovich, I.V, Taran, O.P, Simonov, A.N, Matvienko, L.G, Parmon, V.N. (2011)
Photoinduced catalytic synthesis of biologically important metabolites from
formaldehyde and ammonia under plausible “prebiotic” conditions. Advances in Space
Research. (3)48: 441-449
2. Fox, S.W, Windsor, C.R. (1970). Synthesis of Amino Acids by the Heating of
Formaldehyde and Ammonia. Science. (170)3961: 984-986
Acknowledgements
I would like to thank Professor Csizmadia, Professor Viskolcz and Natalie J. Galant from the Department of Chemistry and the Department of
Medical Biophysics at the University of Toronto for their help and guidance on this research project. Thank you to the University of Szeged for
providing the computational programs needed to complete this calculations necessary. I would also like to thank all my fellow ROP299 candidates for
their support and help while completing this project. I would also like to thank Netflix for keeping me sane, although it did prove a distraction at times,
it gave me support during the late nights of work.
3. Feldmann. T.M, Widicus, S.L, Blake, G.A, Kent IV, D.R, Goddard III, W.A. (2005).
Aminomethanol water elimination: Theoretical examination The Journal of Chemical
Physics. 123: 1-6
4. Wollin. G, Ericson, D.B. (1971). Amino-acid Synthesis from Gases detected in
Interstellar Space. Nature. (223): 615-616
5. Bossa, J.B, Theule, P., Duvernay, F., Chiavassa, T. (2009). NH2CH2OH Thermal
Formation in Interstellar Ices Contribution to the 5-8 μm Region toward Embedded
Protostars. The Astrophysical Journal. 707: 1524-1532
6. Carballeira, L., Perez-Juste, I. (1999). An Ab Initio Interpretation in Gas Phase and
Aqueous Solution of the Generalized Anomeric Effect in R-OCR2-NR2 (R=H, CH3).
Journal of Computational Chemistry. (21)6: 462-477
Ab initio Analysis of the Thermochemical Properties of the Addition Reaction of Methanimine and Ammonia to form Monomethylhydrazine
Skye Daley1, Natalie J. Galant2, Bela Viskolez3, Imre G. Csizmadia1,3
1Department
of Chemistry, University of Toronto
2Department of Medical Biophysics, University of Toronto
2Department of Chemical Informatics, University of Szeged, Hungary
INTRODUCTION
• 
Hydrazines—which includes hydrazides and
hydrazones—has been extensively studied due to
their carcinogenic properties and their ability to
induce tumours in numerous organs and tissues.
They can synthetically be produced but are also
naturally occurring, as is with the case of a methyl
derivative of hydrazine, monomethylhydrazine
(MMH).
Figure 1. General structures of the hydrazine group, monomethylhydrazine, and two
isomers of dimethylhydrazine, respectively.
• 
• 
• 
MMH is produced from the metabolism of the
toxin gyromitrin, found within several members of
the fungal genus Gyromitra, including Gyromitra
esculenta. Once metabolized inside of our bodies,
MMH breaks down into organic free radicals which
have the ability to cause damage to the genome and
proteome. Previous studies have found the
administration of MMH to induce lung neoplasms
and tumours in several tissue types in mice
populations.
MMH and other hydrazines are of interest to the
scientific community due to their exothermic
reactivity in the presence of a catalyst, and high
energy content. They are synthetically produced
primarily for use in industrial chemicals, including
fuel for rockets and missiles.
MMH can be synthesized through multiple
reactions. However, this study analyzed a
simplified theoretical reaction for the synthesis of
monomethylhydrazine, which features
methaniamine and ammonia as the reactants.
CONCLUSION
METHODOLOGY
• 
• 
• 
• 
Gaussian 09 and Gaussview was used to in tandem to generate input files for the reactants,
transition states, and products.
From these input files, the geometric optimization of the molecules was obtained using the
Density Functional Theory through both the B3LYP/6-31G(d) and G3MP2B3 levels of theory.
Such molecules underwent calculation under both aqueous and vacuum conditions.
Thermochemical properties of the reaction – including Gibbs free energy, total energy, and
enthalpy – were calculated, and the Gibbs free energy was plotted.
A 1D scan was also generated to measure the change in energy correlated with 30 degree
rotations of monomethylhydrazine.
RESULTS
• 
• 
• 
The addition of ammonia to methanimine to create
monomethylhydrazine is an endergonic, exothemic
chemical reaction.
Given the instability of the product molecule and the
high activation energy barrier present in this
theoretical reaction, it is unlikely that this reaction
would occur naturally and without a reaction
catalyst.
The scan demonstrates that the anti conformation of
the product monomethylhydrazine occupies an
energy maxima, and the gauche conformation
occupies an energy minima (and therefore is
favoured).
REFERENCES
Figure 2. B3LYP reaction coordinate of the addition reaction of
methanimine and ammonia in a vacuum.
Figure 4. B3LYP reaction coordinate of the addition reaction of
methanimine and ammonia in aqueous conditions.
Figure 3. G3MP2B3 reaction coordinate of the addition reaction of
methanimine and ammonia in a vacuum.
Figure 5. G3MP2B3 reaction coordinate of the addition reaction of
methanimine and ammonia in aqueous conditions.
[1] Toth B. (1975). Synthetic and naturally occurring hydrazines as possible cancer
causative agents. Cancer Res. 35(12):3693.
[2] Toth B., Patil K. (1981). Gyromitrin as a tumor inducer. Neoplasma 28(5):
559-564.
[3] Bergman K., Hellenas K. (1992). Methylation of rat and mouse DNA by the
mushroom poision gyromitrin and its metabolite monomethylhydrazine. Cancer
Letters. 61(2):165-170.
[4] Nagel D., Wallace L., Toth B., Kupper R. (1977). Formation of methylhydrazine
from acetaldehyde N-methyl-N-formylhydrazone, a component of Gyromitra
esculenta. Cancer Res. 37(9):3458-3460.
[5] Sun H., Law C.K. (2007). Thermochemical and kinetic analysis of the thermal
decomposition of monomethylhydrazine: an elementary reaction mechanism. J Phys
Chem A. 111(19):3748-3760.
[6] Catoire L., Chaumeix N., Paillard C. (2004). Chemical kinetic model for
monomethylhydrazine/nitrogen tetraoxide gas phase combustion and hypergolic
ignition. J Propul Power. 20(1):87-92.
[7] Frisch, M. J., et al. (2009). Gaussian 09, Revision A.02. Gaussian 09, Revision A.
02.
ACKNOWLEDGEMENT
Figure 2. Theoretical reaction mechanism of the one-step addition of methanimine and
ammonia. Figure 6. 1D scan of the rotation of monomethylhydrazine around its dihedral.
We would like to thank the Department of Chemistry and the Research
Opportunity Program (ROP299) at the University of Toronto for providing
the opportunity to undertake the research project. Furthermore, we would
like to thank the University of Szeged for providing the software enabling
the energy calculations. Craig Yu, Johnson Li, and Jay Lee for general
support and technical assistance. Ab Ini%o Op%miza%on of Addi%on of Water to Methanimine to Form Aminomethanol Sudarshan Bala, Natalie J Galant, Béla Viskolcz, Imre G. Csizmadia
Department of Chemistry, University of Toronto
Abstract Results •  Op$mal reac$on energies for the hydra$on of methanimine to produce aminomethanol in both solvated and unsolvated condi$ons were calculated using both the B3LYP/6-­‐31(d) and G3MP2B3 levels of theory. Water was used as the solvent. •  The forward reac$on was thermodynamically favourable using the B3LYP/
6-­‐31(d) method, with an energy difference of -­‐22.35 kJ/mol between the product and the reactants in vacuum, and an energy difference of -­‐9.21 kJ/mol when solvated in water. •  The same reac$on was found to be unfavourable when calculated using the G3MP2B3 level of theory, with an energy difference of +4.24 kJ/mol between the product and reactants in vacuum, and an energy difference of +16.26 kJ/mol when solvated in water. •  The reac$on was found to be spontaneous, exergonic, and exothermic using the B3LYP/6-­‐31(d) theory, but unspontaneous, endergonic, and exothermic using the G3MP2B3 level of theory. •  Entropy was found to decrease for both levels of theory, and for both the solvated condi$on and in vacuum. NH
+
O
H
methanimine
Figure 1 Aminomethanol Figure 2 Methanimine H
water
HO
NH 2
aminomethanol
Figure 3 Reac$on Scheme Methodology • Ini$al structures of methanimine, water, aminomethanol, and the transi$on state of the reac$on were generated using Molecular GaussView 5.0 soZware. Setup Reac%on Coordinates Figure 4 B3LYP/6-­‐31(d) Reac$on Coordinate of Hydra$on of Methanimine In Vacuum Setup • Gaussian 09 soZware was used to geometrically op$mize each molecule using a B3LYP/6-­‐31(d) level of theory ini$ally, and then Op$miza$on a G3MP2B3 level of theory. Figure 5 B3LYP/6-­‐31(d) Reac$on Coordinate of Hydra$on of Solvated Methanimine Enthalpy & Entropy Changes Enthalpy Changes ∆H in Vacuum (kJ/
mol) Figure 7 G3MP2B3 Reac$on Coordinate of Hydra$on of Solvated Methanimine Figure 4 Figure 5 Figure 6 Figure 7 B3LYP/6-­‐31(d) model of hydra$on of methanimine in vacuum. ∆G = -­‐22.35 kJ/mol: the reac$on is thermodynamically favourable B3LYP/6-­‐31(d) model of hydra$on of methanimine solvated in water. ∆G = -­‐9.21kJ/mol: the reac$on is thermodynamically favourable G3MP2B3 model of hydra$on of methanimine in vacuum. ∆G = 4.24 kJ/mol: the reac$on is thermodynamically unfavourable G3MP2B3 model of hydra$on of methanimine solvated in water. ∆G = 16.26 kJ/mol: the reac$on is thermodynamically unfavourable References: Data Analysis • Reac$on coordinate diagrams were generated for the reac$ons, and op$mized thermodynamic values (∆S, ∆H, and ∆G) were calculated for each reac$on. Figure 8 2-­‐D Poten$al Energy Scan of Aminomethanol Figure 6 G3MP2B3 Reac$on Coordinate of Hydra$on of Methanimine In Vacuum • Calcula$ons were setup for each molecule in both solvated and unsolvated condi$ons, with water as the solvent. Addi$onally, a Calcula$on 2D scan was setup for aminomethanol in unsolvated condi$ons Poten%al Energy Scan [1] Woon D. (1999). Ab ini&o quantum chemical studies of reac&ons in astrophysical ices. Icarus. 142:550-­‐556. [2] Feldmann M, Widicus S, Blake G, Kent D, Goddard W. (2005). Aminomethanol water elimina&on: Theore&cal examina&on. J Chem Phys. 123(3). [3] Danger G, Duvernay F, Theulé P, Borget F, Chiavassa T. (2012). Hydroxyacetonitrile (HOCH2CN) forma&on in astrophysical condi&ons, compe&&on with the aminomethanol, a glycine precursor. Astrophys J. 756(1). [4] Szori M, Jojart B, Izsak R, Szori K, Csizmadia I.G., Viskolcz B. (2011). Chemical evolu&on of biomolecule building blocks. Can thermodynamics explain the accumula&on of glycine in the prebio&c ocean? Roy Soc Ch. 16(13);7449-­‐7458. [5] Yelle R, Vuimon V, Lavvas P, Klippenstein S, Smith M, Horst S, Cui J. (2010). Forma&on of NH3 and CH2NH in Titan’s upper atmosphere. Faraday Discuss. 147; 31-­‐49. [6] Bunkan A, Tang Y, Sellevag S, Nielsen C. (2014). Atmospheric gas phase chemistry of CH2=NH and HNC, a first-­‐principles approach. J Phys Chem-­‐Us. 118(28); 5279-­‐5288. [7] Layer, R. W. (1963). Chemistry of imines. Chem Rev. 63(5); 489−510. Acknowledgements: We would like to thank the Department of Chemistry and the ROP299 Research Opportunity Program for enabling this research project. We would also like to thank Craig Yu, Johnson Li, and Jay Lee for providing mo$va$onal and technical support. Finally, we would like to thank the University of Szeged for providing the computa$onal power used to perform the calcula$ons. -­‐40.6611 ∆H in Water (kJ/mol) Entropy Changes -­‐28.1034 ∆S in Vacuum (Cal/
mol-­‐Kelvin) -­‐36.224 ∆S in Water (Cal/mol-­‐
Kelvin) -­‐36.238 Table 1 G3MP2B3 Op$mized Enthalpy and Entropy Changes Conclusions •  Both B3LYP/6-­‐31(d) and G3MP2B3 models indicated that the hydra$on of methanimine was an exothermic reac$on. •  The reac$on was spontaneous and exergonic when calculated using the B3LYP/6-­‐31(d) method, and unspontaneous and endergonic when calculated using the G3MP2B3 method. •  The entropy of the reac$on was nega$ve in all cases, indica$ng that entropy decreased throughout the reac$on. The op$mized entropy values did not vary significantly between the solvated and vacuum states. •  The change in enthalpy in vacuum was greater than the change in enthalpy in solvated condi$ons, which indicated that the reac$on released more heat when taking place in vacuum Ab initio study of the reaction of Carbon monoxide with Ammonia to form Formamide
Cheng Min Sung1, Natalie J Galant1,2, Bela Viskolz1,3, Imre G. Csizmadia1,3
1. Department of Chemistry, University of Toronto, Ontario
2. Department of Medical Biophysics, University of Toronto, Ontario
3. Department of Chemistry and Chemical Informatics, University of Szeged, Hungary
Result and Discussion
Introduction
Formamide, also called methanamide, is widely used as an
alternative solvent to water due to its large dipole moment and
neutral pH of 7.1 [1]. In addition, formamide can serve as
important intermediate and reagent in multiple industrial chemistry
processes such as Pellizzari reaction that produces a common
pharmaceutical compound 1,2,4-triazoles [2].
As the simplest form of peptide bond molecule, formamide
can be used as a prototype in peptide bond formation. In particular,
reaction of protonated formamide with methanium creates feasible
source of acetamide in interstellar medium, which can be linked to
origin of life [3]. Peptide bond plays a key role in many biological
processes and is essential for protein synthesis.
In this study, direct synthesis of formamide in vacuum from
the reaction of carbon monoxide with ammonia was evaluated
Figure 1. reaction of carbon monoxide with ammonia to form
formamide
Methods
Through computational method, the optimized
conformations of CO, H3N, formamide, and the transitions state
of the reaction were found under B3LYP method for comfirmation
of structure, and then under G3MP2B3 methods for more
accurately level of calculation. Basis set of B3LYP method were
in 6-31G(d).
Gaussian 09W and Gaussview 5.0 were used for all
calculations [4]. Thermodynamic values were calculated under
CPCM in the solvent of water and in vacuum. The Hartree
energies calculated were converted into kJ/mol.
Potential energy scanning for formamide were conducted
at the O-C-N-H dihedral for 10 degrees each step in the total of
36 steps in order to find the correct conformation of product
formed.
Figure 3. Reaction progress of CO with H3N in vacuum and in water to form formamide
under G3MP2B3 method.
Calculations of reaction progress (shown in Figure 3) shows the reaction is slightly
exergonic with the forward Gibbs free energy of -3.62kJ/mol in water and slightly
endergonic with the forward Gibbs free energy of 8.83kJ/mol in vacuum. The activation
energy is 344.85kJ/mol in water, and 344.28kJ/mol in vacuum. Other important
thermodynamic values calculated include forward ΔH of -42.50kJ/mol in water, and 27.85kJ/mol in vacuum. Entropy was also calculated with -31.3729.60 Cal/mol*K in water,
and -29.60 Cal/mol*K in vacuum.
The result of formamide dihedral O-C-N-H scan (shown in Figure 4.) reveals that
planar conformation has 83.15kj/mol lower in Gibbs free energy, and therefore, more
favorable than tetrahedral conformation. This large difference, and therefore planar
formamide may be the only product observed.
Conclusion
In Figure 3, both reaction progress have high activation energy with the values around
344kJ/mol, meaning the formation of formamide by reacting CO with H3N may require
catalyst for faster reaction. Also, the comparison in Figure 3 indicates that molecules are
more stable in solvent of water than in vacuum, this is due to the fact that polar bonds of
water molecules stabilize polar products and reactants. Lastly, the forward reaction shows
that the reaction is theoretically more favorable in water than in vacuum, although not
considerably.
According to the scanning dihedral graph, structure of formamide occurs to be planar.
This is due to the partial double bond formed between carbon and nitrogen.
Figure 2. Dihedral bond in formamide (D), showing O-C-N-H
dihedral bond.
The thermodynamic information of the reaction calculated in this study may provide an
insight to predict possible outcomes for future reaction studies involving formamide. In
addition, further research regarding formamide to form essential peptide bonds, which links
to the origin of life, can be performed more efficiently.
Figure 4. 1-D Scan of dihedral angle O-C-N-H of formamide in 10 degrees each step
for the total of 36 steps.
References
1.Höhn A, and by Staff U. (2014). Formamide. Kirk-Othmer Encyclopedia of
Chemical Technology. 1–10.
2. Wang Z. (2010). Shi Epoxidation. Comprehensive organic name
reactions and reagents. 585:2590-93
3. Redondo P, Barrientos C, Largo A. (2014). Peptide bond formation through
gas-phase reactions in the interstellar medium: formamide and acetamide
as prototype. The Astrophysical Journal. 793: doi:10.1088/0004637X/793/1/32
4. Frishch J, Trush W, Schleger HB, Scuceria E, Robb A, Cheesman R.
Gaussian 09, Revision A.1. Gaussian, inca. Wallingford Ct, 2009
Acknowledgements
We acknowledge the opportunity for this computational research given by
Department of Chemistry and the Research Opportunity Program at University
of Toronto; we thank Alicia Park, Alice Xu, Jay Lee, Johnson Li, and Craig Yu
for their general support and technical assistance.